Retroviral protease inhibiting compounds

ABSTRACT

A compound of the formula: ##STR1## is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.

This is a continuation-in-part of U.S. patent application Ser. No.08/572,226, filed Dec. 13, 1995, now abandoned.

TECHNICAL FIELD

The present invention relates to novel compounds and a composition andmethod for inhibiting retroviral proteases and in particular forinhibiting human immunodeficiency virus (HIV) protease, a compositionand method for inhibiting a retroviral infection and in particular anHIV infection, processes for making the compounds and syntheticintermediates employed in the processes.

BACKGROUND OF THE INVENTION

Retroviruses are those viruses which utilize a ribonucleic acid (RNA)intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase,reverse transcriptase, during their life cycle. Retroviruses include,but are not limited to, the RNA viruses of the Retroviridae family, andalso the DNA viruses of the Hepadnavirus and Caulimovirus families.Retroviruses cause a variety of disease states in man, animals andplants. Some of the more important retroviruses from a pathologicalstandpoint include human immunodeficiency viruses (HIV-1 and HIV-2),which cause acquired immune deficiency syndrome (AIDS) in man, humanT-cell lymphotrophic viruses I, II, IV and V, which cause human acutecell leukemia, and bovine and feline leukemia viruses which causeleukemia in domestic animals.

Proteases are enzymes which cleave proteins at specific peptide bonds.Many biological functions are controlled or mediated by proteases andtheir complementary protease inhibitors. For example, the protease renincleaves the peptide angiotensinogen to produce the peptide angiotensinI. Angiotensin I is further cleaved by the protease angiotensinconverting enzyme (ACE) to form the hypotensive peptide angiotensin II.Inhibitors of renin and ACE are known to reduce high blood pressure invivo. An inhibitor of a retroviral protease will provide a therapeuticagent for diseases caused by the retrovirus.

The genomes of retroviruses encode a protease that is responsible forthe proteolytic processing of one or more polyprotein precursors such asthe pol and gag gene products. See Wellink, Arch. Virol. 981 (1988).Retroviral proteases most commonly process the gag precursor into coreproteins, and also process the pol precursor into reverse transciptaseand retroviral protease. In addition, retroviral proteases are sequencespecific. See Pearl, Nature 328 482 (1987).

The correct processing of the precursor polyproteins by the retroviralprotease is necessary for the assembly of infectious virions. It hasbeen shown that in vitro mutagenesis that produces protease-defectivevirus leads to the production of immature core forms which lackinfectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al.,Virology 145 280 (1985). Therefore, retroviral protease inhibitionprovides an attractive target for antiviral therapy. See Mitsuya, Nature325 775 (1987).

Current treatments for viral diseases usually involve administration ofcompounds that inhibit viral DNA synthesis. Current treatments for AIDSinvolve administration of compounds such as 3'-azido-3'-deoxythymidine(AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyinosine (DDI), d4T and3TC and compounds which treat the opportunistic infections caused by theimmunosuppression resulting from HIV infection. None of the current AIDStreatments have proven to be totally effective in treating and/orreversing the disease. In addition, many of the compounds currently usedto treat AIDS cause adverse side effects including low platelet count,renal toxicity and bone marrow cytopenia.

Recently the HIV protease inhibitors ritonavir, saquinavir and indinavirhave been approved in the U.S. for treatment of HIV infections. However,there is a continuing need for improved HIV protease inhibitors.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there is a compound of theformula I: ##STR2## wherein R₁ and R₂ are independently selected fromthe group consisting of loweralkyl, cycloalkylalkyl and arylalkyl;

R₃ is loweralkyl, hydroxyalkyl or cycloalkylalkyl;

R₄ is aryl or heterocyclic;

R₅ is ##STR3## wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, Xis O, S or NH, Y is --CH₂ --, --O--, --S-- or --N(R₆)-- wherein R₆ ishydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y"is --CH₂ -- or --N(R_(6"))-- wherein R_(6") is hydrogen, loweralkyl,cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R_(6'))--wherein R_(6') is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl,aryl or arylalkyl, and Z is O, S or NH;

and

L₁ is

a) --O--,

b) --S--,

c) --N(R₇)-- wherein R₇ is hydrogen, loweralkyl, cycloalkyl orcycloalkylalkyl,

d) --O-alkylenyl-,

e) --S-alkylenyl-

f) --S(O)-alkylenyl-,

g) --S(O)₂ -alkylenyl-,

h) --N(R₇)-alkylenyl- wherein R₇ is defined as above,

i) -alkylenyl-O--,

j) -alkylenyl-S--,

k) alkylenyl-N(R₇)-- wherein R₇ is defined as above,

l) alkylenyl or

m) alkenylenyl;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Preferred compounds are compounds of the formula I wherein R₁ and R₂ arearylalkyl, R₃ is loweralkyl, R₄ is aryl, R₅ is ##STR4## wherein X, Y,Y', Y", Z, R_(6"), n, m and m' are defined as above and L₁ is--O-alkylenyl.

More preferred compounds are compounds of the formula I wherein R₁ andR₂ are benzyl or R₁ is benzyl and R₂ is loweralkyl, R₃ is loweralkyl, R₄is (a) phenyl which is substituted with two loweralkyl groups and whichis optionally substituted with a third substituent selected from thegroup consisting of loweralkyl, hydroxy, amino and halo or (b) pyridylor pyrimidinyl either of which is substituted with two loweralkyl groupsand which is optionally substituted with a third substituent selectedfrom the group consisting of loweralkyl, hydroxy, amino and halo, R₅ is##STR5## wherein n is 1 or 2, X is O or S and Y is --CH₂ or --NH--,##STR6## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O, ##STR7##wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR8## wherein m' is1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR9## wherein X is O andR_(6") is hydrogen and

L₁ is --O--CH₂ --.

Even more preferred compounds are compounds of the formula I wherein R₁and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ is loweralkyl,R₄ is 2,6-dimethylphenyl which is optionally substituted with a thirdsubstituent selected from the group consisting of loweralkyl and halo,R₅ is ##STR10## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR11## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR12## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR13##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR14##wherein X is O and R_(6") is hydrogen and

L₁ is --O--CH₂ --.

Most preferred compounds are compounds of the formula I wherein R₁ andR₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ is loweralkyl, R₄is 2,6-dimethylphenyl which is optionally substituted with a thirdsubstituent selected from the group consisting of loweralkyl and halo,R₅ is ##STR15## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR16## wherein m' is 1, X is O, Z is O and Y is --NH--,##STR17## wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or##STR18## wherein X is O and R_(6") is hydrogen and

L₁ is --O--CH₂ --.

Most highly preferred compounds are compounds of the formula I whereinR₁ and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ isloweralkyl, R₄ is 2,6-dimethylphenyl which is optionally substitutedwith a third substituent selected from the group consisting ofloweralkyl and halo, R₅ is ##STR19## wherein n is 1 or 2, X is O or Sand Y is --CH₂ or --NH-- and

L₁ is --O--CH₂ --.

Examples of highly and most highly preferred compounds of the formula Iare selected from the group consisting of:

(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,4,6-trimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(4-fluoro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2,5-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(3-(2,6-dimethylphenyl)propanoyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(4-aza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane;

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane;and

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(4-aza-4,5-dehydro-1-pyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

The most highly preferred compound of the formula I is(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

In some circumstances it is preferred to be able to prepare(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane (or a pharmaceutically acceptablesalt, ester or prodrug thereof) as an amorphous solid. Such an amorphoussolid can be prepared by dissolving(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane in an organic solvent (for example,ethanol, isopropanol, acetone, acetonitrile and the like) and thenadding the solution to water. Preferably,(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane is dissolved in ethanol (from about 2to about 4 mL/g) and the ethanolic solution is added with stirring towater (from about 10 about 100 mL/g) to provide amorphous(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane.

Another embodiment of the present invention comprises an HIV proteaseinhibiting compound comprising a substituent of the formula II:##STR20## wherein R₃ is loweralkyl, hydroxyalkyl or cycloalkylalkyl; andR₅ is ##STR21## wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, Xis O, S or NH, Y is --CH₂ --, --O--, --S-- or --N(R₆)-- wherein R₆ ishydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl,

aryl or arylalkyl, Y" is --CH₂ -- or --N(R_(6"))-- wherein R_(6") ishydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y'is --N(R_(6'))-- wherein R_(6') is hydrogen, loweralkyl, cycloalkyl,cycloalkylalkyl, aryl or arylalkyl, and Z is O, S or NH.

Preferred compounds are HIV protease inhibiting compounds comprising asubstituent of the formula II wherein R₃ is loweralkyl and R₅ is##STR22## wherein X, Y, Y', Y", Z, R_(6"), n, m and m' are defined asabove.

More preferred compounds are HIV protease inhibiting compoundscomprising a substituent of the formula II wherein R₃ is loweralkyl andR₅ is ##STR23## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR24## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR25## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR26##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR27##wherein X is O and R_(6") is hydrogen.

Even more preferred compounds are HIV protease inhibiting compoundscomprising a substituent of the formula II wherein R₃ is isopropyl andR₅ is ##STR28## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR29## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR30## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR31##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR32##wherein X is O and R_(6") is hydrogen.

Most preferred compounds are HIV protease inhibiting compoundscomprising a substituent of the formula II wherein R₃ is isopropyl andR₅ is ##STR33## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR34## wherein m' is 1, X is O, Z is O and Y is --NH--,##STR35## wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or##STR36## wherein X is O and R_(6") is hydrogen.

Most highly preferred compounds are HIV protease inhibiting compoundscomprising a substituent of the formula II wherein R₃ is isopropyl andR₅ is ##STR37## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--.

Examples of such HIV protease inhibiting compounds include:

cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-phenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide;

cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-thiophenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide;and

4-Amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide;and the like;

or pharmaceutically acceptable salts thereof

Such HIV protease inhibiting compounds comprising a substituent of theformula II can be prepared by coupling a suitable intermediate orprecursor having an amino group (--NH₂ or --NHR* wherein R* isloweralkyl), a hydroxyl group (--OH) or a thiol group (--SH) to thecompound of the formula III or a salt or an activated ester derivativethereof: ##STR38## wherein R₃ is loweralkyl, hydroxyalkyl orcycloalkylalkyl; and R₅ is ##STR39## wherein n is 1, 2 or 3, m is 1, 2or 3, m' is 1 or 2, X is O, S or NH, Y is --CH₂ --, --O--, --S-- or--N(R₆)-- wherein R₆ is hydrogen, loweralkyl, cycloalkyl,cycloalkylalkyl, aryl or arylalkyl, Y" is --CH₂ -- or --N(R_(6"))--wherein R_(6") is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl,aryl or arylalkyl, Y' is --N(R_(6'))-- wherein R_(6') is hydrogen,loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, and Z is O,S or NH.

Preferred compounds are compounds of the formula III or an activatedester derivative thereof wherein R₃ is loweralkyl and R₅ is ##STR40##wherein X, Y, Y', Y", Z, R_(6"), n, m and m' are defined as above.

More preferred compounds are compounds of the formula III or anactivated ester derivative thereof wherein R₃ is loweralkyl and R₅ is##STR41## wherein n is 1 or 2, X is O or S and Y is --CH₂ or --NH--,##STR42## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR43## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR44##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR45##wherein X is O and R_(6") is hydrogen.

Even more preferred compounds are compounds of the formula III or anactivated ester derivative thereof wherein R₃ is isopropyl and R₅ is##STR46## wherein n is 1 or 2, X is O or S and Y is --CH₂ or --NH--,##STR47## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR48## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR49##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR50##wherein X is O and R_(6") is hydrogen.

Most preferred compounds are compounds of the formula III or anactivated ester derivative thereof wherein R₃ is isopropyl and R₅ is##STR51## wherein n is 1 or 2, X is O or S and Y is --CH₂ or --NH--,##STR52## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR53##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR54##wherein X is O and R_(6") is hydrogen.

Most highly preferred compounds are compounds of the formula III or anactivated ester derivative thereof wherein R₃ is isopropyl and R₅ is##STR55## wherein n is 1 or 2, X is O or S and Y is --CH₂ or --NH--.

The compounds of the invention can comprise asymmetrically substitutedcarbon atoms. As a result, all stereoisomers of the compounds of theinvention are meant to be included in the invention, including racemicmixtures, mixtures of diastereomers, as well as single diastereomers ofthe compounds of the invention.

The terms "S" and "R" configuration are as defined by the IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.Chem. (1976) 45, 13-30.

The term "N-protecting group" or "N-protected" as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undersirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene and Wuts, "Protective Groups In Organic Synthesis,"(John Wiley & Sons, New York (1991)), which is hereby incorporated byreference. N-protecting groups comprise acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) andbenzyloxycarbonyl (Cbz).

The term "activated ester derivative" as used herein refers to acidhalides such as acid chlorides, and activated esters including, but notlimited to, formic and acetic acid derived anhydrides, anhydridesderived from alkoxycarbonyl halides such as isobutyloxycarbonylchlorideand the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimidederived esters, N-hydroxybenzotriazole derived esters,N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,2,4,5-trichlorophenol derived esters, thiophenol derived esters,propylphosphonic acid derived anhydrides and the like.

The term "alkanoyl" as used herein refers to R₁₉ C(O)-- wherein R₁₉ is aloweralkyl group.

The term "alkenylenyl" as used herein refers to a divalent group derivedfrom a straight or branched chain hydrocarbon containing from 2 to 10carbon atoms and also containing at least one carbon-carbon double bond.Examples of alkenylene include --CH═CH--, --CH₂ CH═CH--, --C(CH₃)═CH--,--CH₂ CH═CHCH₂ --, and the like.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₁₅ O-- andR₁₅ S--, respectively, wherein R₁₅ is a loweralkyl group.

The term "alkoxyalkoxy" as used herein refers to R₂₂ O--R₂₃ O-- whereinR₂₂ is loweralkyl as defined above and R₂₃ is an alkylenyl group.Representative examples of alkoxyalkoxy groups include methoxymethoxy,ethoxymethoxy, t-butoxymethoxy and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group appendedto a loweralkyl radical.

The term "alkoxycarbonyl" as used herein refers to R₂₀ C(O)-- whereinR₂₀ is an alkoxy group.

The term "alkylamino" as used herein refers to --NHR₁₆ wherein R₁₆ is aloweralkyl group.

The term "alkylaminocarbonyl" as used herein refers to R₂₁ C(O)--wherein R₂₁ is an alkylamino group.

The term "alkylenyl" as used herein refers to a divalent group derivedfrom a straight or branched chain saturated hydrocarbon having from 1 to10 carbon atoms by the removal of two hydrogen atoms, for examplemethylene (--CH₂ --), 1,2-ethylene (--CH₂ CH₂ --), 1,1-ethylene═CH--CH₃, 1,3-propylene (--CH₂ CH₂ CH₂ --), 2,2-dimethylpropylene (--CH₂C(CH₃)₂ CH₂ --), and the like.

The term "aminocarbonyl" as used herein refers to --C(O)NH₂.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclicring system comprising 6 to 12 carbon atoms and having one or twoaromatic rings including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can beunsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, halo, haloalkyl, haloalkoxy,alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino,aminocarbonyl, mercapto, nitro, carboxaldehyde, carboxy and hydroxy.

The term "arylalkyl" as used herein refers to an aryl group aspreviously defined, appended to a loweralkyl radical, for example,benzyl and the like.

The term "cycloalkyl" as used herein refers to an aliphatic ring systemhaving 3 to 8 carbon atoms including, but not limited to, cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl groupappended to a loweralkyl radical, including but not limited tocyclohexylmethyl.

The term "dialkylamino" as used herein refers to --NR₁₆ R₁₇ wherein R₁₆and R₁₇ are independently selected from loweralkyl groups.

The term "dialkylaminocarbonyl" as used herein refers to R₂₂ C(O)--wherein R₂₂ is a dialkylamino group.

The term "halo" or "halogen" as used herein refers to --Cl, --Br, --I or--F.

The term "haloalkoxy" as used herein refers to R₁₈ O-- wherein R₁₈ is ahaloalkyl group.

The term "haloalkyl" as used herein refers to a loweralkyl group inwhich one or more hydrogen atoms are replaced by halogen, for example,chloromethyl, chloroethyl, trifluoromethyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as usedherein refers to any 3- or 4-membered ring containing a heteroatomselected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-memberedring containing one, two or three heteroatoms independently selectedfrom the group consisting of nitrogen, oxygen and sulfur or a 5-memberedring containing 4 nitrogen atoms; and includes a 5-, 6- or 7-memberedring containing one, two or three nitrogen atoms; one oxygen atom; onesulfur atom; one nitrogen and one sulfur atom; one nitrogen and oneoxygen atom; two oxygen atoms in non-adjacent positions; one oxygen andone sulfur atom in non-adjacent positions; two sulfur atoms innon-adjacent positions; two sulfur atoms in adjacent positions and onenitrogen atom; two adjacent nitrogen atoms and one sulfur atom; twonon-adjacent nitrogen atoms and one sulfur atom; two non-adjacentnitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 doublebonds and the 6- and 7-membered rings have 0-3 double bonds. Thenitrogen heteroatoms can be optionally quaternized. The term"heterocyclic" also includes bicyclic groups in which any of the aboveheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, benzofuryl, bistetrahydorfuranyl or benzothienyl andthe like). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl,pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl,thienyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl,isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Heterocyclics alsoinclude compounds of the formula ##STR56## wherein X* is --CH₂ --,--NH-- or --O--, Y* is --C(O)-- or --C(R")₂ --!_(v) wherein R" ishydrogen or C₁ -C₄ -alkyl and v is 1, 2 or 3 and Z* is --O-- or --NH--;such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.

Heterocyclics can be unsubstituted or substituted with one, two, threeor four substituents independently selected from the group consisting ofhydroxy, halo, oxo (═O), alkylimino (R*N═ wherein R* is a loweralkylgroup), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy,haloalkyl, cycloalkyl, aryl, arylalkyl, --COOH, --SO₃ H and loweralkyl.In addition, nitrogen containing heterocycles can be N-protected.

The term "hydroxyalkyl" as used herein refers to a loweralkyl radical towhich is appended an hydroxy group.

The term "loweralkyl" as used herein refers to a straight or branchedchain alkyl radical containing from 1 to 6 carbon atoms including, butnot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl,2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy groupappended to a loweralkyl radical.

The compound of the invention of formula I can be prepared as shown inSchemes I-IV. As outlined in Scheme I, intermediates 1 and 2 (wherein P₁is an N-protecting group, for example, t-butyloxycarbonyl) can becoupled using standard peptide coupling reagents and methods, forexample, reaction of 1 and 2 in the presence of 1-hydroxybenzotriazoleand a diimide such as dicyclohexylcarbodiimide (DCC) orN-ethyl-N'-dimethylaminopropyl carbodiimide (EDAC) and the like to give3. Alternatively, a salt or an activated ester derivative ofintermediate 1 (for example, the acid chloride, prepared by reaction ofthe carboxylic acid with thionyl chloride) can be reacted withintermediate 2.

Compound 3 can be N-deprotected to give compound 4. N-deprotection of 3wherein P₁ (especially wherein P₁ is t-butyloxycarbonyl) is an acidlabile N-protecting group can lead to formation of impurities resultingfrom migration of the acyl group R₄ --L₁ --C(O)-- from the amino groupto the hydroxyl group. The formation of this impurity can be minimizedor eliminated by performing the deprotection using (1) trifluoroaceticacid in methylene chloride or (2) concentrated hydrochloric acid (fromabout 2 molar equivalents to about 6 molar equivalents, preferably, fromabout 2 molar equivalents to about 4 molar equivalents) in acetic acidat about room temperature. A preferred N-deprotection method comprisesreacting compound 3 (wherein P₁ is t-butyloxycarbonyl) with concentratedhydrochloric acid (from about 10 to about 20 molar equivalents) inacetonitrile (from about 2 to about 10 liters/kilogram of compound 3) ata temperature of from about 0° C. to about 5° C. Compound 5 or anactivated ester derivative thereof can then be coupled to compound 4 togive the compound of the formula I (i.e., 6).

An alternative process is shown in Scheme IIA. Compound 7 (wherein P₂ isan N-protecting group, for example, benzyloxycarbonyl) can be coupled tocompound 5, or a salt or an activated ester derivative thereof (forexample, the acid chloride, prepared by reaction of the carboxylic acidwith thionyl chloride), to give 8. Compound 8 can be N-deprotected togive 9. Compound 9 can be coupled with compound 1, or an activated esterderivative thereof, to give the compound of the formula I (i.e., 6).

Scheme IIB shows a preferred alternative process wherein the N-protectedamino alcohol 7a (P₃ is hydrogen and P₄ is an N-protecting group or bothP₃ and P₄ are N-protecting groups, preferably, P₃ and P₄ are benzyl) isreacted with from about 1 to about 1.3 molar equivalents of carboxylicacid 5 or a salt or an activated ester derivative thereof (for example,the acid chloride, prepared by reaction of the carboxylic acid withthionyl chloride in ethyl acetate or THF or oxalyl chloride intoluene/DMF and the like) in the presence of from about 1.0 to about 4.0molar equivalents (preferably, from about 2.5 to about 3.5 molarequivalents) of an organic amine base (for example, imidazole,1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole,4-methylimidazole, 4-nitroimidazole, pyridine,N,N-dimethylaminopyridine, 1,2,4-triazole, pyrrole, 3-methylpyrrole,triethylamine or N-methylmorpholine and the like) or from about 1 toabout 20 molar equivalents of an inorganic base (for example, sodiumcarbonate or sodium bicarbonate and the like) in an inert solvent (forexample, ethyl acetate, dimethylformamide, THF, acetonitrile, isopropylacetate or toluene and the like) at a temperature of from about 0° C. toabout 50° C. to provide compound 8a. Preferred organic amine basesinclude imidazole and 1,2,4-triazole.

N-Debenzylation of 8a (for example, using hydrogen and a hydrogenationcatalyst or Pd/C and a formic acid salt (for example, ammonium formateand the like) or Pd/C and formic acid and the like) provides 9. Compound9 can be advantageously purified by crystallization with an organiccarboxylic acid (for example, S-pyroglutamic acid, succinic acid orfumaric acid and the like). A preferred organic carboxylic acid isS-pyroglutamic acid.

Compound 9 (or an organic carboxylic acid salt of compound 9) is reactedwith from about 1.0 to about 1.3 molar equivalents of carboxylic acid 1or a salt or an activated ester derivative thereof (for example, theacid chloride) in the presence of (1) from about 4 to about 8 molarequivalents (preferably, from about 5 to about 7 molar equivalents) ofan inorganic base (for example, NaHCO₃, Na₂ CO₃, KHCO₃, K₂ CO₃, NaOH orKOH and the like) in an inert solvent (for example, 1:1 ethylacetate/water or isopropyl acetate/water or toluene/water or THF/waterand the like) at about room temperature or (2) from about 1.0 to about4.0 molar equivalents (preferably, from about 2.5 to about 3.5 molarequivalents) of an organic amine base (for example, imidazole,1-methylimidazole, 2-methylimidazole, 2-isopropylimidazole,4-methylimidazole, 4-nitroimidazole, pyridine,N,N-dimethylaminopyridine, 1,2,4-triazole, pyrrole, 3-methylpyrrole,triethylamine or N-methylmorpholine and the like) in an inert solvent(for example, ethyl acetate, isopropyl acetate, THF, toluene,acetonitrile, dimethylformamide and the like) at a temperature of fromabout 0° C. to about 50° C. to provide compound 6.

In a preferred embodiment of the invention (shown in Scheme III),intermediate compound 5 has the formula of compound 10 (R₃ is as definedfor the compound of formula I and is preferably isopropyl). Compound 10can be prepared in variety ways as shown in Scheme III. In one method,amino acid 11 (either as the free carboxylic acid or as the carboxylicacid ester (i.e., loweralkyl ester)) is converted to carbamate 12 (R" isphenyl, loweralkyl-substituted phenyl, halo-substituted phenyl,nitro-substituted phenyl, trifluoromethylphenyl and the like) byreaction with the appropriate chloroformate ester and the like. Reactionof carbamate 12 with from about 1.0 to about 1.5 molar equivalents ofamine 13 or an acid addition salt thereof (Q is a leaving group, forexample, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate,p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent(for example, THF, methyl t-butyl ether, dimethoxyethane, THF/water,dimethoxyethane/water, toluene or heptane and the like) in the presenceof a base (for example, LiOH, NaOH, Li₂ CO₃, Na₂ CO₃, lithium phenoxideor sodium phenoxide and the like) in the amount of from about 2.5 toabout 3.5 molar equivalents provides urea 14. Urea 14 can be isolatedand reacted further or can be converted in situ to cyclic urea 10 byreaction in an inert solvent (for example, THF, dimethoxyethane, methylt-butyl ether, toluene or heptane and the like) with a base (forexample, potassium t-butoxide, sodium hydride, potassium hydride ordimethylaminopyridine and the like) in the amount of from about 2.0 toabout 5.0 molar equivalents. If the amino acid ester of 11 was thestarting material, the ester is then hydrolyzed to provide thecarboxylic acid 10.

Alternatively, amino acid 11 (either as the free carboxylic acid or asthe carboxylic acid ester) is converted to urea 14 by reaction with fromabout 1.0 to about 1.5 molar equivalents of isocyanate 15 (Q is aleaving group, for example, Cl, Br or I, or a sulfonate such asmethanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and thelike) in an inert solvent (for example, THF, dimethoxyethane, methylt-butyl ether, toluene or heptane and the like) in the presence of abase.

In yet another alternative, amino acid 11 (either as the free carboxylicacid or as the carboxylic acid ester) is converted to diamine 16 byreaction with from about 1.0 to about 1.5 molar equivalents of amine 13or an N-protected derivative thereof (Q is a leaving group, for example,Cl, Br or I, or a sulfonate such as methanesulfonate, triflate,p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent(for example, THF, dimethoxyethane, methyl t-butyl ether, toluene orheptane and the like) in the presence of a base (for example, NaH orpotassium t-butoxide and the like) in the amount of from about 1.0 toabout 4.0 molar equivalents. N-deprotection is required if theN-protected derivative of 13 was used. Reaction of diamine 16 with acarbonyl equivalent 17 (for example, phosgene, carbonyldiimidazole andthe like wherein Q' and Q" are leaving groups such as Cl, Br, I,--O-loweralkyl, --O-aryl or imidazolyl and the like) in an inert solvent(for example, THF, dimethoxyethane, methyl t-butyl ether, toluene orheptane and the like) in the presence of a base (for example, NaH orpotassium t-butoxide and the like and the like) in the amount of fromabout 2.0 to about 4.0 molar equivalents provides cyclic urea 10. If theamino acid ester of 11 was the starting material, the ester is thenhydrolyzed to provide the carboxylic acid 10.

In yet another alternative shown in Scheme IV, compound 11 (either asthe free carboxylic acid or as the carboxylic acid ester (i.e.,loweralkyl ester)) is reacted with acrylonitrile according to J. Am.Chem. Soc. 72, 2599 (1950) to give aminonitrile 18. Alternatively,acrylonitrile can be replaced with 3-chloropropionitrile to provide 18.N-protection of aminonitrile 18 as the carbamate (R₃₀ is loweralkyl orphenyl or haloalkyl (for example, 2-chloroethyl, 2-bromoethyl and thelike) and the like) using standard conditions (for example, reaction ofthe amine with the appropriate chloroformate ester (CIC(O)OR₃₀ whereinR₃₀ is loweralkyl, phenyl, haloalkyl and the like) neat or in an inertsolvent (for example, water, THF and the like) in the presence of aninorganic base (for example, NaOH, KOH, K₂ CO₃ and the like) or anorganic base (for example, an alkylamine or dialkylamine and the like)and the like) provides compound 19. Hydrogenation of 19 in the presenceof a catalyst (for example, Ni--Al alloy (basic) or Raney nickel(neutral or basic) or PtO₂ (acidic) and the like) in an inert solvent(for example, water or methanol or ethanol or THF and the like) providescyclic urea 10. In a preferred process, compound 19 is hydrogenated inthe presence of a Ni--Al alloy catalyst in an inert solvent (forexample, water or methanol or ethanol or THF and the like) in thepresence of a base (for example, KOH or NaOH or LiOH or an organic aminebase and the like) in the amount of from about 1.1 to about 5 molarequivalents to provide cyclic urea 10. If the amino acid ester of 11 wasthe starting material, the ester is then hydrolyzed to provide thecarboxylic acid 10.

Alternatively, hydrogenation of compound 18 (as described above forcompound 19) provides diamine 16 which can be converted to compound 10as previously described. If the amino acid ester of 11 was the startingmaterial, the ester is then hydrolyzed to provide the carboxylic acid10. ##STR57##

Key intermediates for the preparation of the compounds of the inventioninclude compounds of the formula III as described above and compounds ofthe formula IV: ##STR58## or a salt thereof, wherein P₃ and P₄ areindependently selected from hydrogen or an N-protecting group;

R₁ and R₂ are independently selected from the group consisting ofloweralkyl, cycloalkylalkyl and arylalkyl;

R₃ is loweralkyl, hydroxyalkyl or cycloalkylalkyl; and

R₅ is ##STR59## wherein n is 1, 2 or 3, m is 1, 2 or 3, m' is 1 or 2, Xis O, S or NH, Y is --CH₂ --, --O--, --S-- or --N(R₆)-- wherein R₆ ishydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y"is --CH₂ -- or --N(R_(6"))-- wherein R_(6") is hydrogen, loweralkyl,cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, Y' is --N(R_(6'))--wherein R_(6') is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl,aryl or arylalkyl, and Z is O, S or NH.

Preferred compounds are compounds of the formula IV wherein P₃ and P₄are hydrogen or benzyl, R₁ and R₂ are arylalkyl, R₃ is loweralkyl and R₅is ##STR60## wherein X, Y, Y', Y", Z, R_(6"), n, m and m' are defined asabove.

More preferred compounds are compounds of the formula IV wherein R₁ andR₂ are benzyl or R₁ is benzyl and R₂ is loweralkyl, R₃ is loweralkyl andR₅ is ##STR61## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR62## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR63## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR64##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR65##wherein X is O and R_(6") is hydrogen.

Even more preferred compounds are compounds of the formula IV wherein R₁and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ is loweralkyland R₅ is ##STR66## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR67## wherein m is 1 or 2, X is O, Y is --CH₂ -- and Z is O,##STR68## wherein m' is 1, X is O, Z is O and Y is --NH--, ##STR69##wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or ##STR70##wherein X is O and R_(6") is hydrogen.

Most preferred compounds are compounds of the formula IV wherein R₁ andR₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ is loweralkyl andR₅ is ##STR71## wherein n is 1 or 2, X is O or S and Y is --CH₂ or--NH--, ##STR72## wherein m' is 1, X is O, Z is O and Y is --NH--,##STR73## wherein m' is 1, X is O, Y" is --NH-- and Y' is --NH-- or##STR74## wherein X is O and R_(6") is hydrogen.

Most highly preferred compounds are compounds of the formula IV whereinR₁ and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ isloweralkyl and R₅ is ##STR75## wherein n is 1 or 2, X is O or S and Y is--CH₂ or --NH--.

Preferred salts of the compound of formula IV are organic carboxylicacid salts, especially the (S)-pyroglutamic acid salt.

The following examples will serve to further illustrate the preparationof the novel compounds of the invention.

EXAMPLE 1 (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

A. N,N-Dibenzyl-(L)-phenylalanine Benzyl Ester

A solution containing L-phenylalanine (161 kg, 975 moles), potassiumcarbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), andbenzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24hours. The reaction mixture was cooled to 60° C. and the lower aqueouslayer was removed. Heptane (850 L) and water (385 L) were added to theorganics, stirred, and the layers separated. The organics were thenwashed once with a water/methanol mixture (150 L/150 L). The organicswere then stripped to give the desired product as an oil, which wascarried on in the next step without purification.

IR (neat) 3090, 3050, 3030, 1730, 1495, 1450, 1160 cm⁻¹, ¹ H NMR (300MHz, CDCl₃) δ7.5-7.0 (m, 20H), 5.3 (d, 1H, J=13.5 Hz), 5.2 (d, 1H,J=13.5 Hz), 4.0 (d, 2H, J=15 Hz), 3.8 (t, 2H, J=8.4 Hz), 3.6 (d, 2H,J=15 Hz), 3.2 (dd, 1H, J=8.4, 14.4 Hz), ¹³ C NMR (300 MHz, CDCl₃)δ172.0, 139.2, 138.0, 135.98.2, 128.1, 128.1, 126.9, 126.2, 66.0, 62.3,54.3, 35.6. α!_(D) -79° (c=0.9, DMF).

B. (4S)-4-(N,N-Dibenzylamino)-3-oxo-5-phenyl-pentanonitrile

A solution containing the product of Example 1A (i.e., benzyl ester)(approx. 0.45 moles) in 520 mL tetrahydrofuran and 420 mL acetonitrilewas cooled to -40° C. under nitrogen. A second solution containingsodium amide (48.7 g, 1.25 moles) in 850 mL tetrahydrofuran was cooledto -40° C. To the sodium amide solution was slowly added 75 mLacetonitrile and the resulting solution was stirred at -40° C. for morethan 15 minutes. The sodium amide/acetonitrile solution was then slowlyadded to the benzyl ester solution at -40° C. The combined solution wasstirred at -40° C. for one hour and then quenched with 1150 mL of a 25%(w/v) citric acid solution. The resulting slurry was warmed to ambienttemperature and the organics separated. The organics were then washedwith 350 mL of a 25% (w/v) sodium chloride solution, then diluted with900 mL heptane. The organics were then washed three times with 900 mL ofa 5% (w/v) sodium chloride solution, two times with 900 mL of a 10%methanolic water solution, one time with 900 mL of a 15% methanolicwater solution, and then one time with 900 mL of a 20% methanolic watersolution. The organics were stripped and the resulting materialdissolved into 700 mL of hot ethanol. Upon cooling to room temperature,the desired product precipitated. Filtration gave the desired product in59% yield from the L-phenylalanine. IR (CHCl₃) 3090, 3050, 3030, 2250,1735, 1600, 1490, 1450, 1370, 1300, 1215 cm⁻¹, ¹ H NMR (CDCl₃) δ7.3 (m,15H), 3.9 (d, 1H, J=19.5 Hz), 3.8 (d, 2H, J=13.5 Hz), 3.6 (d, 2H, J=13.5Hz), 3.5 (dd, 1H, J=4.0, 10.5 Hz), 3.2 (dd, 1H, J=10.5, 13.5 Hz), 3.0(dd, 1H, J=4.0, 13.5 Hz), 3.0 (d, 1H, J=19.5 Hz), ¹³ C NMR (300 MHz,CDCl₃) δ197.0, 138.4, 138.0, 129.5, 129.0, 128.8, 128.6, 127.8, 126.4,68.6, 54.8, 30.0, 28.4. α!_(D) -95° (c=0.5, DMF).

C. (5S)-2-Amino-5-(N,N-dibenzylamino)-4-oxo-1,6-diphenylhex-2-ene

To a -5° C. solution of the nitrile product of Example 1B (90 Kg, 244moles) in tetrahydrofuran (288 L), was added benzylmagnesium chloride(378 Kg, 2M in THF, 708 moles). The solution was warmed to ambienttemperature and stirred until analysis showed no starting material. Thesolution was then recooled to 5° C. and slowly transferred to a solutionof 15% citric acid (465 kg). Additional tetrahydrofuran (85 L) was usedto rinse out the original container and the rinse was added to thecitric acid quench container. The organics were separated and washedwith 10% sodium chloride (235 kg) and stripped to a solid. The productwas stripped again from ethanol (289 L) and then dissolved in 80° C.ethanol (581 L)). After cooling to room temperature and stirring for 12hours, the resulting product was filtered and dried in a vacuum oven at30° C. to give approx. 95 kg of the desired product. mp 101-102° C., IR(CDCl₃) 3630, 3500, 3110, 3060, 3030, 2230, 1620, 1595, 1520, 1495, 1450cm⁻¹, ¹ H NMR (300 MHZ, CDCl₃) d 9.8 (br s,1 H), 7.2 (m, 20H), 5.1 (s,1H), 4.9 (br s, 1H), 3.8 (d, 2H, J=14.7 Hz), 3.6 (d, 2H, J=14.7 Hz), 3.5(m, 3H), 3.2 (dd, 1H, J=7.5, 14.4 Hz), 3.0 (dd, 1H, J=6.6, 14.4 Hz), ¹³C NMR (CDCl₃) d 198.0, 162.8, 140.2, 140.1, 136.0, 129.5, 129.3, 128.9,128.7, 128.1, 128.0, 127.3, 126.7, 125.6, 96.9, 66.5, 54.3, 42.3, 32.4.α!_(D) -147° (c=0.5, DMF).

D. (2S,3S,5S)-5-Amino-2-(N,N-dibenzylamino)-3-hydroxy-1,6-diphenylhexane

i) A suspension of sodium borohydride (6.6 kg, 175 moles) intetrahydrofuran (157 L) was cooled to less than -10±5° C.Methanesulfonic acid (41.6 kg, 433 moles) was slowly added and thetemperature kept below 0° C. during the addition. Once the addition wascomplete, a solution of water (6 L, 333 moles), the product of Example1C (20 kg, 43 moles) and tetrahydrofuran (61 L) was slowly added whilemaintaining the temperature below 0° C. during the addition. The mixturewas stirred for not less than 19 h at 0±5° C.

ii) To a separate flask was added sodium borohydride (6.6 kg, 175 moles)and tetrahydrofuran (157 L). After cooling to -5±5° C., trifluoroaceticacid (24.8 kg, 218 moles) was added while maintaining the temperaturebelow 15° C. The solution was stirred 30 min at 15±5° C. and was thenadded to the reaction mixture resulting from step i, keeping thetemperature at less than 20° C. This was stirred at 20±5° C. untilreaction was complete. The solution was then cooled to 10±5° C. andquenched with 3N NaOH (195 kg). After agitating with tert-butyl methylether (162 L), the organic layer was separated and washed one time with0.5N NaOH (200 kg), one time with 20% w/v aqueous ammonium chloride (195kg), and two times with 25% aqueous sodium chloride (160 kg). Theorganics were stripped to give the desired product as an oil which wasused directly in the next step.

IR (CHCl₃) 3510, 3400, 3110, 3060, 3030, 1630, ¹ H NMR (300 MHz, CDCl₃)δ7.2 (m, 20H), 4.1 (d, 2H, J=13.5 Hz), 3.65 (m, 1H), 3.5 (d, 2H, J=13.5Hz), 3.1 (m, 2H), 2.8 (m, 1H), 2.65 (m, 3H), 1.55 (m, 1H), 1.30 (m, 1H),¹³ C NMR (300 MHz, CDCl₃) δ140.8, 140.1, 138.2, 129.4, 129.4, 128.6,128.4, 128.3, 128.2, 126.8, 126.3, 125.7, 72.0, 63.6, 54.9, 53.3, 46.2,40.1, 30.2.

E.(2S,3S,5S)-2-(N,N-Dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

To a solution of the2S,3S,5S!-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane(approx. 105 kg, 226 moles) in MTBE (1096 L), was added BOC Anhydride(65 kg, 373 moles) and 10% potassium carbonate (550 kg). This mixturewas stirred until reaction was complete (approx. 1 hour). The bottomlayer was removed and the organics were washed with water (665 L). Thesolution was then stripped to give the desired product as an oil. 300MHz ¹ H NMR (CDCl₃) δ1.40 (s,9H), 1.58 (s, 2H), 2.45-2.85 (m, 4H), 3.05(m, 1H), 3.38 (d, 2H), 3.6 (m, 1H), 3.79 (m, 1H), 3.87 (d, 2H), 4.35 (s,1H), 4.8 (s, broad, 1H), 7.0-7.38 (m, 20H).

F-1.(2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

To a stirred solution of2S,3S,5S!-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane(12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate(8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). Thesolution was stirred under nitrogen at 60° C. for three hours and thenat 75° C. for 12 hours. An additional amount of ammonium formate (6 g)and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacialacetic acid. The reaction was driven to completion within 2 hours at areflux temperature. The reaction mixture was then cooled to roomtemperature and then filtered through a bed of celite. The filter cakewas washed with methanol (75 mL) and the combined filtrates wereconcentrated under reduced pressure. The residue was taken up in 1N NaOH(300 mL) and extracted into methylene chloride (2×200 mL). The combinedorganic layers were washed with brine (250 mL) and dried over sodiumsulfate. Concentration of the solution under reduced pressure providedthe desired product as a light colored oil which slowly crystallizedupon standing (5 g). Further purification of the product could beaccomplished by flash chromatography (silica gel, 5% methanol inmethylene chloride). 300 MHz ¹ H NMR (CDCl₃) δ1.42 (s, 9H), 1.58 (m,1H), 1.70 (m,1H), 2.20 (s, broad, 2H), 2.52 (m,1H), 2.76-2.95 (m, 4H),3.50 (m, 1H), 3.95 (m,1H), 4.80 (d, broad,1H), 7.15-7.30 (m,10H).

F-2.2S,3S,5S!-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexanesuccinate salt

To a solution of2S,3S,5S!-2-N,N-dibenzylamino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane(approx. 127 kg, 225 moles) in methanol (437 L), was added a methanolic(285 L) slurry of 5% palladium on carbon (24 kg). To this was added asolution of ammonium formate (84 kg, 1332 moles) in methanol (361 L).The solution was heated to 75° C. for 6-12 hours and then cooled to roomtemperature. Solids were filtered from the reaction mixture using afilter coated with filteraid (Celite) and the methanol was stripped fromthe reaction mixture using heat and vacuum (up to 70° C.). The residuewas dissolved in isopropyl acetate (4400 kg) with heat (40° C.) and thenwashed with a 10% sodium carbonate solution (725 kg), and finally withwater (665 L). Both of the washes were performed at 40° C. to keep theproduct in solution. The solvent was removed under vacuum with heat (upto 70° C.). Isopropyl alcohol (475 L) was then added and stripped off toremove residual solvents. Isopropanol (1200 L) was added to the residueand stirred until homogeneous. To this solution was added a solution ofsuccinic acid (15-40 kg) in isopropanol (1200 L). The solution jacketwas heated to 70° C. to dissolve all of the solids and then allowed toslowly cool to room temperature and stir for 6 hours. The solution wasthen filtered to give the desired product as a white solid (55-80 kg).

mp: 145-146° C. ¹ H NMR: (Me₂ SO-d₆, 300 MHz) δ0.97 (d, 3H, IPA), 1.20(s, 9H), 1.57 (t, 2H), 2.20 (s, 2H, succinic acid), 2.55 (m, 2H), 2.66(m, 2H), 2.98 (m, 1H), 3.42 (m, 1H), 3.70 (m, 1H), 3.72 (m, 1H, IPA),6.60 (d, 1H, amide NH), 7.0-7.3 (m, 10H).

¹ H NMR: (CD₃ OD, 300 MHz) δ1.11 (d, 3H, J=7 Hz, IPA), 1.29 (s, 9H),1.70 (m, 2H), 2.47 (s, 2H, succinic acid), 2.65 (m, 2H), 2.85 (m, 2H),3.22 (m,1H), 3.64 (m, 1H), 3.84 (m,1H), 7.05-7.35 (m,10H).

G. Ethyl 2,6-dimethylphenoxy acetate

To a solution of 2,6-dimethylphenol (8.0 g, 66 mmole) in dioxane (600ml) was added ethyl bromoacetate (18.2 ml, 164 mmole) and cesiumcarbonate (58 g, 176 mmole). The reaction mixture was heated at refluxfor 18 h, cooled to room temperature, filtered and concentrated invacuo. Purification by silica gel column chromatography (5% to 20% etherin hexane) provided the desired compound (80%). 300 MHz ¹ H NMR (CDCl₃)δ1.35 (t, J=7.5 Hz, 3H), 2.30 (s, 6H), 4.31 (q, J=7.5 Hz, 2H), 4.40 (s,2H), 7.0 (m, 3H).

H. 2,6-Dimethylphenoxy acetic acid

To a solution of the compound from Example 1G (5.15 g, 24.7 mmole) inmethanol (170 ml) and water (56 ml) was added 5.3 g of lithium hydroxideat 0° C., the solution was stirred for 1.5 h at RT and concentrated invacuo. The residue was acidified with 0.5M HCl and extracted with ethylacetate (300 ml). The organic layer was dried and concentrated to give awhite solid (4.05 g, 91%). 300 MHz ¹ H NMR (CDCl₃) δ2.30 (s, 6H), 4.48(s, 2H), 7.0 (m, 3H).

I.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

Coupling of the amine from Example 1F with the acid from Example 1Husing standard EDAC coupling procedure provided the desired compound(78%). 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.65 (m, 3H), 2.18 (s,6H), 2.78 (m, 2H), 2.98 (d, J=9 Hz, 2H), 3.75 (m, 1H), 3.90 (m, 1H),4.15 (m, 1H), 4.20 (s, 2H), 4.60 (m,1H), 7.0 (m, 3H), 7.25 (m,10H). Massspectrum: (M=H)⁺ =547.

J. 2-N-(Benzyloxycarbonyl)amino-acetaldehyde

To a solution of 1.45 ml of DMSO in 20 ml of CH₂ Cl₂ at -78° C. wasadded dropwise 1.34 ml of oxalyl chloride. After 15 minutes at -78° C.,a solution of N-Cbz-aminoethanol in 40 ml of CH₂ Cl₂ was added. After 15minutes at -78° C. and 2 minutes at 0° C., the solution was cooled to-78° C. and triethylamine (6.14 ml) was added dropwise. The solution wasstirred at -78° C. for 30 minutes and poured into 50 ml of cold 10% aq.citric acid and extracted with ether (150 ml). The combined organiclayer was washed with brine and dried with anhydrous Na₂ SO₄ ; filteredand concentrated in vacuo. Purification of the crude product by silicagel column chromatography (10% EtOAc/CH₂ Cl₂) provided the desiredcompound (42%). 300 MHz ¹ H NMR (CDCl₃) δ4.17 (d, J=6 Hz, 2H), 5.15 (s,2H), 5.40 (br s,1H), 7.36 (m, 5H), 9.66 (s, 1H). Mass spectrum: (M+NH₄)⁺=211.

K. N-(Benzyloxycarbonylamino)-ethyl valine methyl ester

To a solution of the aldehyde from Example 1J (0.829 g, 4.29 mmole) in17 ml of methanol was added valine methyl ester hydrochloride (0.72 g,4.29 mmole), sodium acetate (0.7 g, 8.58 mmole), and sodiumcyanoborohydride (0.54 g, 8.58 mmole. The mixture was stirred at RTovernight and the solvent was evaporated in vacuo. The residue was takenup in ethyl acetate (100 ml) and washed with satd. NaHCO₃ (10 ml) andthe aq. layer was extracted with ethyl acetate (2×50 ml). The combinedorganic layer was washed with brine and dried with anhy. sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (20% EtOAc/CH₂ Cl₂) to provide the desiredcompound (60%). 300 MHz ¹ H NMR (CDCl₃) δ0.91 (d, J=3 Hz, 3H), 0.94 (d,J=3 Hz, 3H), 1.90 (m, 1H), 2.55 (m, 1H), 2.80 (m, 1H), 2.98 (d, J=6 Hz,1H), 3.20 (m, 1H), 3.30 (m, 1H), 3.71 (s, 3H), 5.10 (s, 2H), 5.27 (br s,1H), 7.37 (m, 5H). Mass spectrum: (M+H)⁺ =309.

L. 2S-(1-Imidazolidin-2-onyl)-3-methyl butanoic acid methyl ester

The Cbz-protecting of the compound in Example 1K was removed byhydrogenolysis and the crude product was treated with one equivalent of1,1,-carbonyldiimidazole in CH₂ Cl₂ to provide the desired compound(64%), 300 MHz ¹ H NMR (CDCl₃) δ0.95 (d, J=7.5 Hz, 3H), 0.98 (d, J=7.5Hz, 3H), 2.15 (m, 1H), 3.47 (m, 3H), 3.71 (s, 3H), 3.73 (m, 1H), 4.23(d, J=10.5 Hz, 1H), 4.81 (br s,1H), Mass spectrum: (M+H)⁺ =201.

M. 2S-(1-Imidazolidin-2-onyl)-3-methyl butanoic acid

To a solution of the compound from Example 1L (151 mg, 0.75 mmole) in2.5 ml of water and 5 ml of dioxane was added at 0° C. lithium hydroxidemonohydrate (2.0 eq.). The solution was stirred at 0° C. for 1.5 h andRT for 1 h. Acidification with 1N HCl, extraction with EtOAc (100ml+2×50 ml), dried with sodium sulfate and evaporation of the filteredsolution in vacuo provided the desired compound (88%). 300 MHz ¹ H NMR(DMSO-d₆) δ0.85 (d, J=12 Hz, 3H), 0.92 (d, J=12 Hz, 3H), 2.05 (m, 1H),3.25 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 3.90 (d, J=15 Hz, 1H), 6.40(br s, 1H), 12.60 (br s, 1H). Mass spectrum: (M+H)⁺ =187.

N.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane

To 4.5 g of the compound from Example 1I was added 40 ml each of CH₂ Cl₂and trifluoroacetic acid. The solution was left at RT for 1 h.Concentration of the solution in vacuo provided the desired compound(100%). 300 MHz ¹ H NMR (CDCl₃) δ1.48 (m, 1H), 1.62 (m, 1H), 2.05 (m,1H), 2.24 (s, 6H), 2.50 (m, 1H), 2.80 (m, 1H), 3.0-3.10 (m, 4H), 3.90(d, J=10 Hz, 1H), 4.17 (m, 1H), 4.26 (ABq, J=13.5 Hz, 2H), 7.0 (m, 3H),7.10 (m, 2H), 7.30 (m, 7H), 7.41 (d, J=10 Hz, 1H). Mass spectrum: (M+H)⁺=447.

O. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the acid fromExample 1M using standard coupling procedure1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in DMF! provided thedesired compound. (80%). 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, J=6 Hz, 3H),0.86 (d, J=6 Hz, 3H), 1.75 (m, 2H), 2.16 (m, 1H), 2.18 (s, 6H), 2.76 (m,2H), 2.97 (d, J=7.5 Hz, 2H), 3.14 (m, 2H), 3.30 (m, 2H), 3.70 (d,J=1-Hz, 1H), 3.75 (m, 1H), 4.20 (m, 4H), 4.50 (br s, 1H), 6.70 (d, J=7.5Hz, 1H), 7.0 (m, 3H), 7.25 (m, 1OH). Mass Spectrum: (M+H)⁺ =615.

EXAMPLE 2 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

Using the procedures described in Examples 1J to 1M, but replacing theN-Cbz-aminoethanol in Example 1J with N-Cbz-3-aminopropanol provided thedesired compound. 300 MHz ¹ H NMR (DMSO-d₆) δ0.82 (d, J=7 Hz, 3H), 0.93(d, J-7 Hz, 3H), 1.77 (m, 2H), 2.10 (m, 1H), 3.10-3.23 (m, 4H), 4.42 (d,J=10.5 Hz, 1H), 6.37 (br s,1H). Mass spectrum: (M+H)⁺ =201.

B. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the acid fromExample 2A using standard procedure (EDAC in DMF) provided the desiredcompound (70%). 300 MHz ¹ H NMR (CDCl₃) δ0.80 (d, J=4.5 Hz, 3H), 0.83(d, J=4.5 Hz, 3H), 1.50 (m, 1H), 1.65-1.72 (m, 6H), 2.20 (s, 6H), 2.68(m, 1H), 2.82 (m, 2H), 3.0 (d, J=7.5 Hz, 1H), 3.05 (m, 4H), 3.77 (m,1H), 4.07 (d, J=4.5 Hz, 1H), 4.20 (m, 4H), 4.50 (br s, 1H), 6.78 (br d,1H), 7.0 (m, 3H), 7.25 (m, 10H). Mass spectrum: (M+H)⁺ =629.

EXAMPLE 3 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(3-oxazolidin-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

A. 2S-(3-Oxazolidin-2-onyl)-3-methyl-butanoic acid methyl ester

To a solution of L-valine methyl ester hydrochloride (7.6 mmole) wasadded a solution of ethylene oxide in ethanol (1.5 equivalent). Thesolution was kept at 0° C. for 0.5 h and then at RT for 18 h, at whichtime 0.01 equivalent of BF₃.Et₂ O was added. Fresh ethylene oxide wasbubbled directly into the solution for 3 to 4 minutes. After 8 h thesolution was concentrated to dryness and the residue was dissolved inCH₂ Cl₂ and cooled to 0° C. To this solution was added 1.2 equivalentsof triethylamine and 1.0 equivalent of triphosgene. After 1 h, thesolvent was removed in vacuo and the residue was washed with water (30ml) and extracted with CH₂ Cl₂ (3×50 ml), dried and concentrated.Purification of the crude product by silica gel column chromatography(5% EtOAc/CH₂ Cl₂) provided the desired compound (42%, 2 steps). 300 MHz¹ H NMR (CDCl₃) δ0.98 (d, J=4.0 Hz, 3H), 1.0 (d, J=4.0 Hz, 3H), 2.16 (m,1H), 3.60 (m, 2H), 3.73 (s, 3H), 4.20 (d, J=10 Hz, 1H), 4.37 (m, 2H).Mass spectrum: (M+H)⁺ =202.

B. 2S-(3-Oxazolidin-2-onyl)-3-methyl-butanoic acid

Hydrolysis of the methyl ester from Example 3A, using the proceduredescribed in Example 1M provided the desired compound. 300 MHz ¹ H NMR(DMSO-d₆) δ0.90 (d, J=6 Hz, 3H), 0.95 (d, J=6 Hz, 3H), 2.1 (m, 1H), 3.55(m, 1H), 3.70 (m, 1H), 3.88 (d, J=9 Hz, 1H), 4.30 (m, 2H), 13.0 (brs,1H). Mass spectrum: (M+NH₄)⁺ =205.

C. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(3-oxazolidin-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

Coupling of the amine from Example 1N with the acid from Example 3Busing standard coupling procedures (EDAC in DMF) provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, J=4.5 Hz, 3H), 0.87 (d,J=4.5 Hz, 3H), 1.75 (m, 1H), 2.10 (m, 1H), 2.20 (s, 6H), 2.65 (m, 1H),2.85 (m, 1H), 3.0 (m, 3H), 3.30 (m, 1H), 3.60 (m, 2H), 3.77 (m, 1H),4.20 (m, 4H), 6.25 (br d, J=6 Hz, 1H), 7.0 (m, 3H), 7.25 (m, 10H). Massspectrum: (M+H)⁺ =616.

EXAMPLE 4 (2S,3S,5S)-2-(3R,3aS,6aR)-Bis-tetrahydrofuranyloxy!amino-3-hydroxy-5-2S-(3-methyl-1-imidazolidin-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. 2S-(3-Methyl-1-imidazolidin-2-onyl)-3-methyl butanoic acid methylester

To a suspension of 45 mg (60% oil dispersion) of sodium hydride in 0.5ml of DMF was added a solution of 150 mg of the compound from Example 1Lin 4.5 ml of DMF. After 20 minutes at RT, (1.5 equivalent, 0.07 ml)methyl iodide was added. Reaction was complete in 1 h. The reaction wasquenched with satd. NH₄ Cl solution and extracted with ether (100 ml+50ml×2), dried and concentrated in vacuo. The crude product was purifiedby silica gel column chromatography (20% EtOAc/CH₂ Cl₂) to provide thedesired compound (61%). 300 MHz ¹ H NMR (CDCl₃) δ0.95 (d, J=6 Hz, 3H),0.97 (d, J=6 Hz, 3H, 2.15 (m, 1H), 2.80 (s, 3H), 3.32 (m, 3H), 3.60 (m,1H), 3.70 (s, 3H), 4.25 (d, J=10.5 Hz, 1H). Mass spectrum: (M+H)⁺ =215.

B. 2S-(3-Methyl-1-imidazolidin-2-onyl)-3-methyl butanoic acid

Hydrolysis of the methyl ester from Example 4A using the proceduredescribed in Example 1M provided the desired compound. 300 MHz ¹ H NMR(DMSO-d₆) δ0.85 (d, J=6 Hz, 3H), 0.92 (d, J=6 Hz, 3H), 2.05 (m, 1H),2.65 (s, 3H), 3.25 (m, 3H), 3.42 (m, 1H), 3.90 (d, J=10 Hz, 1H). Massspectrum: (M+H)⁺ =201.

C. (3R,3aS,6aR)-Bis-tetrahydrofuranyl-(4-nitrophenyl)carbonate

To a solution of 3R-hydroxy-(3aS,6aR)-bis-tetrahydrofuran J. Med. Chem.37, 2506-2508 (1994)! (200 mg, 1.54 mmole) in 10 ml of CH₂ Cl₂ was addedtriethylamine (0.26 ml, 1.85 mmole), and p-nitrophenyl chloroformate(341 mg, 1.69 mmole). The solution was kept at RT for 3 days, dilutedwith CH₂ Cl₂ (100 ml) and washed with satd. NaHCO₃ (15 ml). The organiclayer was dried and concentrated in vacuo. Purification by silica gelcolumn chromatography (5% EtOAc/CH₂ Cl₂) provided the desired compound(42%). 300 MHz ¹ H NMR (CDCl₃) δ2.0 (m, 1H), 2.20 (m, 1H), 3.18 (m, 1H),4.0 (m, 3H), 4.17 (m, 1H), 5.27 (m, 1H), 5.80 (d, J=6 Hz), 7.40 (d,J=7.5 Hz, 2H), 8.30 (d, J=7.5 Hz, 2H). Mass spectrum: (M+NH₄)⁺ =313.

D. (2S,3S,5S)-2-(3R,3aS,6aR)-Bis-tetrahydrofuranyloxy!amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

To a solution of the carbonate from Example 4C (100 mg, 0.34 mmole) in3.4 ml of DMF was added the compound from Example 1F (130 mg, 0.34mmole). The solution was kept at RT overnight and then concentrated invacuo. Purification of the crude product by silica gel columnchromatography (2% to 5% MeOH/CH₂ Cl₂) provided the desired compound(93%). 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.64 (m, 3H), 2.76 (m,2H), 2.87 (m, 2H), 3.66-4.0 (m, 7H), 4.53 (m, 1H), 5.06 (m, 2H), 5.68(d, J=6 HZ, 1H), 7.10-7.28 (m, 10H). Mass spectrum: (M+NH₄)⁺ =558.

E. (2S,3S,5S)-2-(3R,3aS,6aR)-Bis-tetrahydrofuranyloxy!amino-3-hydroxy-5-amino-1,6-diphenylhexane

To a solution of the compound from Example 4D (170 mg, 0.31 mmole) in 5ml of CH₂ Cl₂ was added 5 ml of trifluoroacetic acid. After 0.25 h, thesolvent was removed in vacuo. The residue was dissolved in 100 ml ofEtOAc and washed with satd. NaHCO₃ and then brine, dried andconcentrated to provide the desired compound (91%). 300 MHz ¹ H NMR(CDCl₃) δ1.27-1.60 (m, 4H), 1.75 (m, 2H), 2.47 (m, 1H), 2.80 (m, 1H),2.88 (m, 2H), 3.0 (m, 2H), 3.80 (m, 4H), 4.0 (m, 1H), 5.10 (m, 1H), 5.30(d, J=10.5 Hz, 1H), 5.70 (d, J=6 Hz, 1H), 7.05-7.25 (m, 10H). Massspectrum: (M+H)⁺ =441.

F. (2S,3S,5S)-2-(3R,3aS,6aR)-Bis-tetrahydrofuranyloxy!amino-3-hydroxy-5-2S-(3-methyl-1-imidazolidin-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 4B with the amino compoundfrom Example 4E using standard procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=3H, 3H), 0.85 (d,J=Hz, 3H), 1.65 (m, 1H), 2.77 (s, 3H), 2.85 (m, 3H), 3.17 (m, 2H) 3.47(m, 1H), 3.60 (m, 2H), 3.75 (m, 1H), 3.87 (m, 1H), 4.0 (m, 1H), 4.20 (m,1H), 5.05 (m, 2H), 5.68 (d, J=6 Hz, 1H), 6.45 (br d, J=7.5 Hz, 1H), 7.20(m, 10H). Mass spectrum: (M+H)⁺ =623.

EXAMPLE 5 (2S,3S,5S)-2-(3R,3aS,6aR)-Bis-tetrahydrofuranyloxy!amino-3-hydroxy-5-2S-(1-imidazolidin-2-onyl)-3-methyl butanoyl!amino-1,6-diphenylhexane

Coupling of the amino compound from Example 4E with the carboxylic acidfrom Example 1M using standard procedure (EDAC/DMF) provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.85 (d, J=7 Hz, 3H), 0.88 (d, J=Hz,3H), 1.70 (m, 2H, 2.18 (m, 1H), 2.80 (m, 3H), 2.95 (m, 1H), 3.20 (m,4H), 3.60 (m, 3H), 3.75 (m, 2H), 4.0 (m, 1H), 4.20 (m, 1H), 4.45 (s,1H), 5.10 (m, 2H), 5.67 (d, J=6 Hz, 1H) 6.60 (d, J=7.5 Hz, 1H), 7.20 (m,10H). Mass spectrum: (M+H)⁺ =609.

EXAMPLE 6(2S,3S,5S)-2-(N-((5-Thiazolyl)methoxycarbonyl)amino)-5-((2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)-amino)-3-hydroxy-1,6-diphenylhexane

A. Ethyl 2-Chloro-2-formylacetate

To a three neck 2 L round bottom flask charged with potassium t-butoxide(0.5 mol, 500 mL of a 1M solution in THF) and 500 mL of dry THF cooledto 0° C. was added dropwise from an addition funnel a solution of ethylchloroacetate (0.5 mol, 53.5 mL) and ethyl formate (0.5 mol, 40.4 mL),in 200 mL of THF over 3 hours. After completion of addition, thereaction mixture was stirred for 1 hour and allowed to stand overnight.The resulting solid was diluted with diethyl ether and cooled in an icebath. Then, the pH was lowered to approximately 3 using 6N HCl. Theorganic phase was separated, and the aqueous layer was washed 3 timeswith diethyl ether. The combined ethereal portions were dried overNaSO₄, and concentrated in vacuo. The crude desired compound was storedat -30° C. and used without further purification.

B. Ethyl Thiazole-5-carboxylate

To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours.The solvent was removed in vacuo, and the residue was purified bychromatography (SiO₂, 6 cm o.d. column, 100% CHCl₃, R_(f) =0.25) toprovide 11.6 g (60%) of the desired compound as a light yellow oil. NMR(CDCl₃ δ1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95(s, 1H).

C. 5-(Hydroxymethyl)thiazole

To a precooled (ice bath) three neck 500 mL flask containing lithiumaluminum hydride (2.89 g, 76 mmol) in 250 mL of THF was added ethylthiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwiseover 1.5 hours to avoid excess foaming. The reaction was stirred for anadditional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of15% NaOH, and 8.7 mL of water. The solid salts were filtered, and thefiltrate set aside. The crude salts were heated at reflux in 100 mL ofethyl acetate for 30 minutes. The resulting mixture was filtered, andthe two filtrates were combined, dried over Na₂ SO₄, and concentrated invacuo. The product was purified by silica gel chromatography elutingsequentially with 0% -2% -4% methanol in chloroform, to provide thedesired compound, Rf-0.3 (4% methanol in chloroform), which solidifiedupon standing in 75% yield. NMR (CDCl₃) δ4.92 (s, 2H), 7.78 (s, 1H),8.77 (s, 1H). Mass spectrum: (M+H)⁺ =116.

D. ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate

A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excessN-methyl morpholine in 100 ml of methylene chloride was cooled to 0° C.and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. Afterbeing stirred for 1 h, the reaction mixture was diluted with CHCl₃,washed successively with 1N HCl, saturated aqueous NaHCO₃, and saturatedbrine, dried over NaSO₄, and concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO₂, 1-2% MeOH/CHCl₃, Rf=0.5 in4% MeOH/CHCl₃) to yield 5.9 g (78%) of the desired compound as a yellowsolid. NMR (CDCl₃) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s,1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)⁺ =281.

E.(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-3-hydroxy-1,6-diphenylhexane

Coupling of the amino compound from Example 1F with the carbonate fromExample 6D using the procedure from Example 4D, followed by removal ofthe Boc-protecting group using TFA/CH₂ Cl₂ provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ1.3-1.6 (m, 2H), 2.40 (dd, J=14, 8Hz, 1H), 2.78 (dd, J=5 Hz, 1H), 2.88 (d, J=7 Hz, 2H), 3.01 (m, 1H), 3.72(br q, 1H), 3.81 (br d, J=10 Hz, 1H), 5.28 (s, 2H), 5.34 (br d, J=9 Hz,1H), 7.07 (br d, J=7 Hz, 2H), 7.15-7.35 (m, 8H), 7.87 (s, 1H), 8.80 (s,1H). Mass spectrum: (M+H)⁺ =426.

F.(2S,3S,5S)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-5-((2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)-amino)-3-hydroxy-1,6-diphenylhexane

Coupling of the amino compound from Example 6E with the carboxylic acidfrom Example 1M using standard procedure (EDAC in DMF) provided thedesired compound (52%). 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=7.5 Hz, 3H),0.85 (d, J=7.5 Hz, 3H), 1.65 (m, 2H), 2.15 (m, 1H), 2.70 (m, 3H), 2.85(d, 7.5 Hz, 2H), 3.08 (m, 1H), 3.18 (m, 1H), 3.30 (M, 2H), 3.60 (m, 3H),3.80 (m, 1H), 4.16 (m, 1H), 4.40 (s, 1H), 5.16 (d, J=9 Hz, 1H), 5.24 (s,2H), 6.60 (d, J=9 Hz, 1H), 7.20 (m, 10H), 7.83 (s, 1H), 8.80 (s, 1H).Mass spectrum: (M+H)⁺ =594.

EXAMPLE 7(2S,3S,5S)-2-(N-((5-Thiazolyl)-methoxycarbonyl)amino)-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane

A. 2S-(1-Imidazolidin-2-onyl)-3,3-dimethyl butanoic acid

Using the procedures described in Example 1J to 1M, but replacingL-valine methyl ester with L-t-butyl-leucine methyl ester provided thedesired compound. 300 MHz ¹ H NMR (DMSO-d₆) δ1.0 (s, 9H), 3.22 (t, J=7.5Hz, 2H), 3.55 (q, J=7.5 Hz, 1H), 3.65 (q, J=7.5 Hz, 1H), 4.14 (s, 1H),6.40 (s, 1H), 12.62 (br s, 1H). Mass spectrum: (M+H)⁺ =201.

B.(2S,3S,5S)-2-(N-((5-Thiazolyl)-methoxycarbonyl)amino)-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 6E with the carboxylic acidfrom Example 7A using standard procedure (EDAC in DMF) provided thedesired compound (77%). 300 MHz ¹ H NMR (CDCl₃) δ1.0 (s, 9H), 1.68 (m,2H), 2.60-2.80 (m, 3H), 2.85 (d, J=7.5 Hz, 1H), 3.10 (m, 1H), 3.30 (m,1H), 3.50 (m, 1H), 4.56 (s, 1H), 5.15 (d, J=7.5 Hz, 1H), 5.25 (ABq, 1H),6.50 (d, J=7 Hz, 1H), 7.20 (m, 10H), 7.83 (s, 1H), 8.80 (s, 1H). Massspectrum: (M+H)⁺ =609.

EXAMPLE 8(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the carboxylic acidfrom Example 7A using standard procedure (EDAC in DMF) provided thedesired compound (80%). 300 MHz ¹ H NMR (CDCl₃) δ1.0 (s, 9H), 2.18 (s,6H), 2.68 (m, 1H), 2.80 (m, 1H), 2.98 (m, 3H), 3.10 (m, 1H), 3.27 (q,J=7 Hz, 1H), 3.53 (m, 1H), 3.77 (m, 1H), 4.0 (s, 1H), 4.20 (m, 4H), 6.72(m, 1H), 7.0 (m, 3H), 7.10-7.25 (m, 10H). Mass spectrum: (M+H)⁺ =629.

EXAMPLE 9(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

A. 2S-(1-Imidazolidin-2-thionyl)-3-methyl butanoic acid

Using the same procedures described in Example 1J to 1M, but replacing1,1-carbonyl-diimidazole with 1,1,-thiocarbonyldiimidazole provided thedesired compound. 300 MHz ¹ H NMR (DMSO-d₆) δ0.87 (d, J=6 Hz, 3H), 0.96(d, J=6 Hz, 3H), 2.11 (m, 1H), 3.45 (m, 2H), 3.62 (m, 1H), 3.80 (q, J=9Hz, 1H), 4.80 (d, J=10 Hz, 1H), 8.30 (s, 1H), 12.75 (br s, 1H).

B.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the carboxylic acidfrom Example 9A using standard procedure (EDAC in DMF) provided thedesired compound (53%). 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=6 Hz, 3H),0.93 (d, J=6 Hz, 3H), 1.75 (m, 1H), 2.20 (s, 6H), 2.65 (m, 1H), 2.84 (m,1H), 3.0 (m, 3H), 3.25 (m, 1H), 3.40 (m, 2H), 3.54 (d, J=Hz, 1H), 3.78(m, 1H), 4.22 (m, 4H), 4.56 (d, J=10.5 Hz, 1H), 5.65 (s, 1H), 6.60 (d,J=Hz, 1H), 7.0 (m, 3H), 7.25 (m, 10H). Mass spectrum: (M+H)⁺ =631.

EXAMPLE 10(2S,3S,5S)-2-(4-Amino-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 2,6-Dimethyl-4-nitro phenoxyacetic acid ethyl ester

To a solution of 10.5 g (54.6 mmole) of ethyl 2,6-dimethylphenoxyacetate and 7.5 g (109 mmole) of sodium nitrite in 100 ml of methylenechloride was added 50 ml of trifluoroacetic acid slowly. The reactionmixture became solid after addition. Additional 35 ml of trifluoroaceticacid was added. After the reaction mixture was stirred at roomtemperature for 3 h, it was carefully partitioned between saturatedsodium bicarbonate solution and methylene chloride. The combined organicextracts were washed with brine and dried over anhydrous sodium sulfate,filtered and evaporated to dryness under reduced pressure. The residuewas recrystalized in 30% ethyl acetate and hexanes to give 4.75 g (36%)of ethyl 2,6-dimethyl-4-nitro phenoxyacetate as light yellow prisms. 300MHz ¹ H NMR (CDCl₃) δ1.34 (3H, t, J=7.5 Hz), 2.39 (6H, s), 4.31 (2H, q,J=7.5 Hz), 7.93 (2H, s).

B. 2,6-Dimethyl-4-nitro-phenoxyacetic acid

To a solution of 0.962 g (4.06 mmole) of ethyl 2,6-dimethyl-4-nitrophenoxy acetate in 10 ml of methanol was added 1 ml of 3N sodiumhydroxide. After the reaction mixture was stirred at room temperaturefor 30 minutes it was acidified with 3N HCl and partitioned betweenwater and methylene chloride. The combined organic extracts were washedwith brine and dried over anhydrous sodium sulfate, filtered andevaporated to dryness under reduced pressure to give 0.82 g (97%) of2,6-dimethyl-4-nitro phenoxy acetic acid as light yellow solid. 300 MHz¹ H NMR (d₃ -DMSO) δ2.35 (6H, s), 4.55 (2H, s) 7.97 (2H, s), 13.02 (1H,bs).

C.(2S,3S,5S)-2-(t-Butyloxycarbonyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-only)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of(2S,3S,5S)-2-(t-butyloxycarbonyl)amino-3-hydroxy-5-amino-1,6-diphenylhexanewith the carboxylic acid from Example 1M using standard procedure (EDACin DMF) provided the desired compound (100%). 300 MHz ¹ H NMR (CDCl₃)δ0.83 (d, J=6 Hz, 3H), 0.87 (d, J=6 Hz, 3H), 1.40 (s, 9H), 1.70 (m, 2H),2.16 (m, 1H), 2.58-2.80 (m, 4H), 3.10-3.30 (m, 4H), 3.65 (m, 2H), 4.20(m, 1H), 4.38 (s, 1H), 4.83 (d, J=Hz, 1H), 6.53 (d, J=9 Hz, 1H), 7.20(m, 10H). Mass spectrum: (M+H)⁺ =553.

D.(2S,3S,5S)-2-Amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Deprotection of the Boc-protecting group of the compound from Example10C by standard procedure (TFA/CH₂ Cl₂) provided the desired compound.300 MHz ¹ H NMR (CDCl₃) δ0.87 (d, J=6 Hz, 3H), 0.90 (d, J=6 Hz, 3H),1.33 (d, J=4.5, 9.0 Hz, 1H) 2.18 (m, 1H), 2.50 (m, 1H), 2.80 (m, 5H),3.20 (m, 4H), 3.72 (d, J=10 Hz, 1H), 4.30 (m, 1H), 4.50 (s, 1H), 6.67(d, J=7 Hz, 1H), 7.20 (m, 10H). Mass spectrum: (M+H)⁺ =453.

E.(2S,3S,5S)-2-(4-Nitro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 10D with the carboxylic acidfrom Example 10B using standard procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, 7=Hz, 3H), 0.86 (d,J=7 Hz, 3H), 1.70 (m, 3H), 2.18 (m, 2H), 2.28 (s, 6H) 2.75 (m, 3H),2.95-3.30 (m, 6H), 3.67 (d, J=10.5 Hz, 1H), 3.75 (m, 1H), 3.82 (d, J=4Hz, 1H), 4.25 (m, 5H), 6.55 (d, J=7 Hz, 1H), 7.20 (m, 10H), 7.92 (s,2H). Mass spectrum: (M+H)⁺ =660.

F.(2S,3S,5S)-2-(4-Amino-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

To a suspension of 7 mg of 10% Pd/C in 5 ml of methanol was added asolution of 69 mg of the compound from Example 10E. The reaction mixturewas stirred vigorously under a hydrogen atmosphere (balloon filled withhydrogen attached to a 3-way stopcock). After 1 h, reaction was completeby TLC analysis; the catalyst was filtered off and the filtrate wasconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (2% to 5% MeOH/CH₂ Cl₂) to provide the desiredcompound (65%). 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=Hz, 3H), 0.87 (d,J=6 Hz, 3H), 1.70 (m, 2H), 2.10 (s, 6H), 2.15 (m, 2H), 2.72 (m, 2H),2.97 (d, J=7.5 Hz, 2H), 3.08 (m, 1H), 3.15 (m, 1H), 3.30 (m, 2H), 3.45(br s, 2H), 3.66 (d, J=10 Hz, 1H), 3.72 (m, 1H), 3.90 (d, J=3 Hz, 1H),4.10-4.20 (m, 4H), 4.30 (s, 1H), 6.33 (s, 2H), 6.57 (d, J=9 Hz, 1H),7.20 (m, 10H). Mass spectrum: (M+H)⁺ =630.

EXAMPLE 11(2S,3S,5S)-2-(2,4,6-Trimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

A. 2,4,6-Trimethylphenoxyacetic acid

Using the procedures from Example 1G and 1H, but replacing2,6-dimethylphenol with 2,4,6-trimethylphenol provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ2.25 (s, 9H), 4.43 (s, 2H), 6.84 (s,2H). Mass spectrum: (M+H)⁺ =195.

B.(2S,3S,5S)-2-(2,4,6-Trimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 10D with the carboxylic acidfrom Example 11A using standard procedure (EDAC in DMF) provided thedesired compound (51%). 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=6 Hz, 3H),0.85 (d, J=6 Hz, 3H), 1.70 (m, 4H), 2.13 (s, 6H), 2.25 (s, 3H), 2.75 (m,2H), 2.97 (d, J=7 Hz, 1H), 3.13 (m, 2H), 3.28 (m, 2H), 3.68 (d, J=10 Hz,1H), 3.72 (m, 1H), 4.16 (m, 4H), 4.40 (br s, 1H), 6.67 (d, J=8 Hz, 1H),6.80 (s, 2H), 7.20 (m, 10H). Mass spectrum: (M+H)⁺ =629.

EXAMPLE 12(2S,3S,5S)-2-(4-Fluoro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 4-Fluoro-2,6-dimethylphenoxyacetic acid

Using the procedure from Example 1G and 1H, but replacing2,6-dimethylphenol with 4-fluoro-2,6-dimethylphenol provided the desiredcompound. 300 MHz ¹ H NMR (CD₃ OD) δ2.26 (s, 6H), 4.37 (s, 2H), 6.73 (d,J=9 Hz, 2H). Mass spectrum: M⁺ =198.

B.(2S,3S,5S)-2-(4-Fluoro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 10D with the carboxylic acidfrom Example 12A provided the desired compound. 300 MHz ¹ H NMR (CDCl₃)δ0.83 (d, J=6 Hz, 3H), 0.86 (d, J=6 Hz, 3H), 1.72 (m, 2H), 2.15 (s, 6H),2.20 (m, 1H), 2.76 (m, 2H), 2.98 (d, J=7 Hz, 2H), 3.12 (m, 2H), 3.30 (m,2H), 3.67 (d, J=10 Hz, 1H), 3.72 (m, 1H), 4.13 (AB q, J=8, 9 Hz, 2H),4.20 (m, 2H), 4.37 (s, 1H), 6.64 (d, J=9 Hz, 1H), 6.70 (d, J=Hz, 2H),7.20 (m, 10H). Mass spectrum: (M+H)⁺ =633.

EXAMPLE 13 (2S,3S,5S)-2-(4,6-Dimethylpyrimidin-5-oxy-acetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 4,6-Dimethyl pyrimidin-5-oxy-acetic acid

Using the procedures from Example 1G and 1H, but replacing2,6-dimethylphenol with 5-hydroxy-4,6-dimethylpyrimidine (preparedaccording to Chem. Ber. 93 pg. 1998, 1960) provided the desiredcompound. 300 MHz ¹ H NMR (DMSO-d₆) δ2.45 (s, 6H), 4.55 (s, 2H), 8.50(s, 1H). Mass spectrum: (M+H)⁺ =183.

B. (2S,3S,5S)-2-(4,6-Dimethylpyrimidin-5-oxy-acetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 10D with the carboxylic acidfrom Example 13A provided the desired compound. 300 MHz ¹ H NMR (CDCl₃)δ0.82 (d, J=6 Hz, 3H), 0.85 (d, J=6 Hz, 3H), 1.70 (m, 2H), 2.15 (m, 1H),2.40 (s, 6H), 2.75 (m, 2H), 2.97 (d, J=7 Hz, 2H), 3.12 (m, 2H), 3.30 (m,2H), 3.66 (d, J=10 Hz, 1H), 3.74 (m, 1H), 3.88 (d, J=Hz, 1H), 4.20 (m,4H, 6.62 (d, J=9 Hz, 1H), 7.0 (d, J=9 Hz, 1H), 7.20 (m, 10H), 8.70 (s,1H). Mass spectrum: (M+H)⁺ =617.

EXAMPLE 14 D.(2S,3S,5S)-2-(2,4-Dimethyl-pyridin-3-oxy-acetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane

A. 2,4-Dimethyl-pyridin-3-oxy-acetic acid

Using the procedures from Example 1G and 1H, but replacing2,6-dimethylphenol with 2,4 dimethyl-3-hydroxypyridine (preparedaccording to J. Med. Chem. 35, pg. 3667-3671, 1992) provided the desiredcompound. 300 MHz ¹ H NMR (DMSO-d₆) δ2.26 (s, 3H), 2.42 (s, 3H), 4.44(s, 2H), 7.08 (d, J=5 Hz, 1H), 8.07 (d, J=5 Hz, 1H). Mass spectrum:(M+H)⁺ =182.

B.(2S,3S,5S)-2-(2,4-Dimethyl-pyridin-3-oxy-acetyl)amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1F with the carboxylic acidfrom Example 14A using standard procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.70 (m, 2H),2.18 (s, 3H), 2.40 (s, 3H), 2.77 (m, 2H), 2.98 (d, J=7 Hz, 2H),3.75-3.95 (m, 3H), 4.20 (s, 2H), 4.22 (m, 1H), 4.60 (br d, 1H), 7.0 (d,J=5H, 1H), 7.10 (m, 3H), 7.25 (m, 7H), 8.16 (d, J=5 Hz, 1H). Massspectrum: (M+H)⁺ =548.

C.(2S,3S,5S)-2-(2,4-Dimethyl-pyridin-3-oxy-acetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane

Deprotection of the Boc-group in the compound from Example 14B usingstandard procedure (TFA/CH₂ Cl₂) provided the desired compound. 300 MHz¹ H NMR (CDCl₃) δ1.45 (m, 1H), 1.62 (m, 1H), 2.23 (s, 3H), 2.45 (s, 3H),2.50 (m, 1H), 2.80 (m, 1H), 3.0 (m, 2H), 3.12 (m, 1H), 3.90 (m, 1H),4.18 (m, 1H), 4.25 (ABq, J=9, 12 Hz, 2H), 6.98 (d, J=5 Hz, 1H), 7.10 (m,2H), 7.30 (m, 8H), 8.17 (d, J=5 Hz, 1H). Mass spectrum: (M+H)⁺ =448.

D.(2S,3S,5S)-2-(2,4-Dimethyl-pyridin-3-oxy-acetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3-dimethylbutanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 14C with the carboxylic acidfrom Example 7A using standard procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.0 (s, 9H), 1.70 (m, 3H),2.18 (s, 3H), 2.42 (s, 3H), 2.75 (m, 2H), 3.0 (m, 4H), 3.30 (m, 1H),3.55 (m, 1H), 3.80 (m, 1H), 4.05 (s, 1H), 4.20 (m, 4H), 4.60 (s, 1H),6.70 (d, J=7 Hz, 1H), 6.97 (d, J=5 Hz, 1H), 7.15 (m, 3H), 7.25 (m, 7H),8.17 (d, J=Hz, 1H), Mass spectrum: (M+H)⁺ =630.

EXAMPLE 15(2S,3S,5S)-2-(2,4-Dimethyl-pyridin-3-oxy-acetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the amino compound from Example 14C with the carboxylic acidfrom Example 1M using standard procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=6 Hz, 3H), 0.86(d, J=6 Hz, 3H), 1.75 (m, 3H), 2.15 (m, 1H), 2.18 (s, 3H), 2.40 (s, 3H),2.75 (m, 2H), 2.97 (d, J=7.5 Hz, 2H), 3.20 (m, 4H), 3.70 (d, J-10 Hz,1H), 3.75 (m, 1H), 4.20 (m, 6H), 4.52 (s,1H), 3.75 (m, 1H), 4.20 (m,6H), 4.52 (s, 1H), 6.80 (d, J-7 Hz, 1H), 6.96 (d, J=4.5 Hz, 1H), 7.20(m, 10H), 8.17 (d, J=4.5 Hz, 1H). Mass spectrum: (M+H)⁺ =616.

EXAMPLE 16(2S,3S,5S)-2-(2,6-Dimethylthiophenoxyacetyl)amino-3-hydroxy-5(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 2,6-Dimethylthiophenoxy acetic acid

Using the procedures from Example 1G and 1H, but replacing2,6-dimethylphenol with 2,6-dimethylthiophenol provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ2.56 (s, 6H), 3.40 (s, 2H), 7.10 (m,3H). Mass spectrum: (M+H)⁺ =197.

B.(2S,3S,5S)-2-(2,6-Dimethylthiophenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 16A with the amino compoundfrom Example 10D provided the desired compound. 300 MHz ¹ H NMR (CDCl₃)δ0.82 (d, J=6 Hz, 3H), 0.86 (d, J=6 Hz, 3H), 2.15 (m, 1H), 2.52 (s, 6H),2.70 (m, 4H), 3.10 (m, 2H), 3.30 (m, 4H), 3.60 (m, 2H), 4.0 (m, 1H),4.10 (m, 1H), 4.22 (s, 1H), 6.39 (d, J=7 Hz, 1H), 6.58 (d, J=9 Hz, 1H),7.20 (m, 13H). Mass spectrum: (M+H)⁺ =631.

EXAMPLE 17(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 4-Bromobutanoyl-L-valine methyl ester

To a solution of 1.08 g (8.4 mmole) of L-valine methyl ester in 30 ml ofCH₂ Cl₂ was added 1.36 ml (16.8 mmole) of pyridine, cooled to 0° C. and1.55 g (8.4 mmole) of 4-bromobutanoyl chloride added. The solution wasstirred at 0° C. for 40 minutes and at RT for 1 h. The solution waswashed with satd. NaHCO₃, brine and dried with anhy. Na₂ SO₄ ; filteredand concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (5% EtOAc/CH₂ Cl₂) to provide 1.82 g (77%) ofdesired product. 300 MHz ¹ H NMR (CDCl₃) δ0.92 (d, J=6 Hz, 3H), 0.96 (d,J=6 Hz, 3H) 2.20 (m, 3H), 2.46 (m, 2H), 3.50 (m, 2H), 3.76 (s, 3H), 4.58(dd, J=4,7 Hz, 1H), 5.97 (br d, J=7 Hz, 1H). Mass spectrum: (M+H)⁺ =297.

B. 2S-(1-Pyrrolidin-2-onyl)-3-methyl-butanoic acid

To a solution of 1.49 g (5.3 mmole) of the compound from Example 17A ina mixture of DMF/CH₂ Cl₂ cooled to 0° C. was added 0.234 g (1.1equivalent) of 60% sodium hydride in mineral oil. The mixture was slowlywarmed up to RT and stirred overnight. The mixture was poured into satd.ammonium chloride and extracted with ethyl acetate, dried andconcentrated in vacuo. The crude product was hydrolyzed using lithuimhydroxide as in Example 1H to provide the desired compound. 300 MHz ¹ HNMR (CDCl₃) δ0.96 (d, J=7 Hz, 3H), 1.06 (d, J=7 Hz, 3H), 2.10 (m, 2H),2.40 (m, 1H), 2.50 (t, J=7 Hz, 2H), 3.56 (m, 2H), 4.14 (d, J=10 Hz, 1H).Mass spectrum: (M+H)⁺ =186.

C.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 17B with the amine fromExample 1N using standard procedure (EDAC in DMF) provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.77 (d, J=7 Hz, 3H), 0.83 (d, J=7Hz, 3H), 1.75 (m, 3H), 2.10 (m, 1H), 2.20 (s, 6H), 2.25 (m, 1H), 2.65(m, 1H), 2.85 (m, 1H), 3.0 (d, J=7 Hz, 2H), 3.20 (m, 1H), 3.77 (m, 2H),3.88 (d, J=10 Hz, 1H), 4.20 (m, 3H), 6.30 (d, J=7 Hz, 1H), 6.98 (m, 3H),7.20 (m, 10H). Mass spectrum: (M+H)⁺ =614.

EXAMPLE 18(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2,5-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 2S-(1-Pyrrolidin-2,5-dionyl)-3-methyl-butanoic acid benzyl ester

To a solution of 700 mg (3.38 mmole) of L-valine benzyl ester in 6 ml ofchloroform was added 1 equivalent of succinic anhydride. After 1 h atRT, the solvent was removed in vacuo and the residue was dissolved in 20ml of DMF. To this solution was added 0.52 g of N-hydroxy-benzotriazole,0.68 g of EDAC and 0.52 ml of triethylamine. After 24 h at RT, 20 mg of4-dimethylaminopyridine was added. The solution was left at RT for 3days. After standard work-up, the crude product was purified by silicagel column chromatography to provide 0.25 g of desired product (26%).300 MHz ¹ H NMR (CDCl₃) δ0.84 (d, J=7 Hz, 3H), 1.12 (d, J=7 Hz, 3H),2.70 (m, 1H), 2.71 (s, 4H), 4.45 (d, J=9 Hz, 1H), 5.15 (s, 2H), 7.30 (m,5H).

B. 2S-(1-Pyrrolidin-2,5-dionyl)-3-methyl-butanoic acid

A mixture of 0.245 of the product from Example 18A, 30 mg of 10%palladium on charcoal in 50 ml of methanol was stirred vigorously underhydrogen atmosphere (balloon filled with hydrogen) for 1 h. The catalystwas filtered off and the solvent was removed under vacuum to provide 168mg of the desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.84 (d, J=6 Hz,3H), 1.13 (d, J=6 Hz, 3H), 2.65 (m, 1H), 2.80 (s, 4H), 4.45 (d, J=8 Hz,1H). Mass spectrum: (M+H)⁺ =200.

C.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-pyrrolidin-2,5-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 18B with the amine fromExample 1N using standard procedure (EDAC in DMF) provided the desiredproduct (75%). 300 MHz ¹ H NMR (CDCl₃) δ0.70 (d, J=4 Hz, 3H), 0.72 (d,J=4 Hz, 3H), 1.70 (m, 1H), 2.20 (s, 6H), 2.45 (m, 2H), 2.60 (s, 4H),2.80 (m, 2H), 3.0 (m, 2H), 3.76 (m, 1H), 4.20 (m, 6H), 7.0 (m, 3H), 7.20(m, 10H). Mass spectrum: (M+H)⁺ =628.

EXAMPLE 19(2S,3S,5S)-2-(Trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 2,6-Dimethyl benzaldehyde

Oxidation of 2,6-dimethyl benzyl alcohol by standard Swern oxidationprocedure (oxalyl chloride/DMSO) provided the desired compound. 300 MHz¹ H NMR (CDCl₃) δ2.62 (s, 6H), 7.10 (m, 2H), 7.33 (t, J=7 Hz, 1H), 10.63(s, 1H), Mass spectrum: (M+H)⁺ =135.

B. Trans-3-(2,6-dimethylphenyl)-propenoic acid methyl ester

To a solution of trimethyl phosphonoacetate (149 mg, 0.82 mmole) in 15ml of THF was added 36 mg of sodium hydride (60% in oil). After 15minutes 100 mg of the compound from Example 19A in 2 ml of THF wasadded. After 2 h, the reaction was quenched carefully with water andextracted with ethyl acetate (70 ml), dried and concentrated.Purification of the crude product by silica gel column chromatography(hexane/EtOAc 95:5) provided the desired compound (75%). 300 MHz ¹ H NMR(CDCl₃) δ2.35 (s, 6H), 3.82 (s, 3H), 6.07 (d, J=16 Hz, 1H). 7.10 (m,3H), 7.85 (d, J=16 Hz, 1H). Mass spectrum: (M+NH₄)⁺ =191.

C. Trans-3-(2,6-dimethylphenyl)-propenoic acid

Hydrolysis of the methyl ester from Example 19B using lithium hydroxidein a mixture of methanol and water provided the desired compound (84%).300 MHz ¹ H NMR (CDCl₃) δ2.38 (s, 6H), 6.13 (d, J=16 Hz, 1H), 7.10 (m,3H), 7.96 (d, J=16 Hz, 1H). Mass spectrum: (M+H)⁺ =194.

D.(2S,3S,5S)-2-(Trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(t-butyloxycarbony1,6-diphenylhexane

Coupling of the carboxylic acid from Example 19C with the amine fromExample 1F using standard procedure (EDAC/DMF) provided the desiredcompound (84%). 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.68 (m,1H), 2.34(s, 6H), 2.75 (m, 2H), 2.96 (m, 2H), 3.72 (m, 1H), 3.85 (m, 1H), 4.08(m, 2H), 4.60 (m, 1H), 5.88 (d, J=10 Hz, 1H), 5.94 (d, J=16 Hz, 1H),7.10 (m, 5H), 7.25 (m, 8H), 7.72 (d, J=16 Hz, 1H). Mass spectrum: (M+H)⁺=543.

E.(2S,3S,5S)-2-(Trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Removal of the Boc-protecting group of the compound from Example 19D(TFA/CH₂ Cl₂) and coupling of the resulting amine with the carboxylicacid from Example 2A using standard procedure (EDAC/DMF) provided thedesired compound (73%). 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=6 Hz, 3H),0.87 (d, J=6 Hz, 3H), 1.50 (m, 1H), 1.70 (m, 2H), 2.20 (m, 1H), 2.33 (s,6H), 2.68 (m, 1H), 2.78 (m, 1H), 2.85 (m, 1H), 3.05 (m, 5H), 3.73 (m,1H), 4.17 (m, 1H), 4.30 (d, J=3 Hz, 1H), 4.60 (s, 1H), 5.95 (d, J=15 Hz,1H), 6.0 (d, J=9 Hz, 1H), 6.80 (d, J=7 Hz, 1H), 7.25 (m, 13H), 7.70 (d,J=15 Hz, 1H). Mass spectrum: (M+H)⁺ =625.

EXAMPLE 20(2S,3S,5S)-2-(3-(2,6-Dimethylphenyl)propanoyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 3-(2,6-Dimethylphenyl)propanoic acid methyl ester

A solution of 400 mg of the compound from Example 19B in 25 ml ofmethanol and 40 mg of 10% Pd/C was stirred vigorously under a hydrogenatmosphere (balloon pressure) for 3 h. The catalyst was filtered off andconcentration of the filtrate in vacuo provided the desired compound(98%). 300 MHz ¹ H NMR (CDCl₃) δ2.35 (s, 6H), 2.45 (m, 2H), 2.98 (m,2H), 3.22 (s, 3H), 7.02 (s, 3H). Mass spectrum: (M+H)⁺ =210.

B. 3-(2,6-Dimethylphenyl)propanoic acid

Hydrolysis of the methyl ester from Example 20A, using lithium hydroxidein methanol and water provided the desired compound (93%). 300 MHz ¹ HNMR (CDCl₃) δ2.36 (s, 6H), 2.50 (m, 2H), 3.0 (m, 2H), 7.03 (s, 3H). Massspectrum: (M+NH₄)⁺ =196.

C.(2S,3S,5S)-2-(3-2,6-Dimethylphenyl)propanoyl)amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 20B with the amine fromExample 1F using standard coupling procedure (EDAC/DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.55 (m, 2H),2.20 (m, 2H), 2.30 (s, 6H), 2.74 (m, 2H), 2.85 (m, 4H), 3.66 (m, 1H),3.82 (m, 1H), 3.95 (m, 2H), 4.57 (brd, 1H), 5.66 (d, J=9 Hz, 1H), 7.0(s, 3H), 7.22 (m, 10H). Mass spectrum: (M+H)⁺ =545.

D.(2S,3S,5S)-2-(3-(2,6-Dimethylphenyl)propanoyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Removal of the Boc-protecting group of the compound from Example 20C.using trifluoroacetic acid in CH₂ Cl₂ and coupling of the resultingamine with the carboxylic acid from Example 2A using standard couplingprocedure (EDAC/DMF) provided the desired compound. 300 MHz ¹ H NMR(CDCl₃) δ0.82 (d, J=6 Hz, 3H), 0.86 (d, J=6 Hz, 3H), 1.55 (m, 2H), 1.65(m, 1H), 1.70 (s, 3H), 2.20 (m, 3H), 2.30 (s, 6H), 2.65 (m, 1H), 2.75(m, 1H), 2.86 (m, 5H), 3.10 (m, 3H), 3.68 (m, 1H), 4.10 (m, 4H), 4.63(s, 1H), 5.75 (d, J=7 Hz, 1H), 6.76 (d, J=7 Hz, 1H), 7.0 (m, 3H), 7.20(m, 10H). Mass spectrum: (M+H)⁺ =627.

EXAMPLE 21(2S,3S,5S)-2-(2,6-Dimethyl-4-hydroxy-phenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. 2,6-Dimethyl-4-tert-butyldimethylsilyloxy phenol

To a solution of 2.5 g (14.7 mmole) of 2,6-dimethylquinone in 5 ml ofmethanol was added 200 mg of Pd/C (20%). The reaction mixture wasstirred under 1 atmosphere of hydrogen for overnight. The Pd/C wasremoved over a celite pad, and the solvent was evaporated to drynessunder reduced pressure to give 2.0 g (100%) of2,6-dimethyldihydroquinone as a light yellow oil.

To a solution of 2.0 g (14.7 mmole) of 2,6-dimethyldihydroquinone in 10ml of methylene chloride was added 1.2 g (17.6 mmole) of imidazole and2.2 g (14.7 mmol) of tert-butyldimethylsilyl chloride subsequently at 0°C. After the reaction was complete as indicated by TLC, it waspartitioned between methylene chloride and 1:1 mixture of 3N hydrogenchloride and brine. The organic layer was washed with brine, dried oversodium sulfate, filtered and evaporated to dryness under reducedpressure. Silica gel chromatography using 5% ethyl acetate:hexanes gave1.8 g (49%) of 2,6-dimethyl-4-tert-butyidimethylsilyloxy phenol as awhite solid. 300 MHz ¹ H NMR (CDCl₃) δ0.16 (s, 6H), 0.98 (s, 9H), 2.19(s, 6H), 4.22 (s, 1H), 6.48 (s, 2H). Mass spectrum: (M+H)⁺ =253.

B. Ethyl 2,6-Dimethyl-4-tert-Butyldimethylsilyloxy phenoxyl acetate

A solution of 1.8 g (7.1 mmole) of2,6-dimethyl-4-tert-butyldimethylsilyloxy phenol in 5 ml ofdimethylformamide was treated with 2.0 g (1.43 mmole) of potassiumcarbonate and 830 μl (7.5 mmole) of ethyl bromoacetate. The resultingsolution was heated at 70° C. for 4 hr. After cooled to roomtemperature, the reaction mixture was partitioned between ethyl acetateand 3N hydrogen chloride. The combined organic layer was washed withdiluted brine, dried over magnesium sulfate, filtered, and evaporated invacuo. Silica gel chromatography using 5% ethyl acetate:hexanes gave2.03 g (85%) of ethyl 2,6-dimethyl-4-tert-butyldimethylsilyloxy phenoxylacetate as a light yellow oil. 300 MHz ¹ H NMR (CDCl₃) δ0.17 (s, 6H),0.97 s, 9H), 1.33 (t, 3H, J=6.3 Hz), 2.22 (s, 6H), 4.30 (q, 2H, J=6.3Hz), 4.35 (s, 2H), 6.57 (s, 2H). Mass spectrum: (M+H)⁺ =356.

C. 2,6-Dimethyl-4-Hydroxyl phenoxyacetic acid

To a solution of 2.03 g (6.0 mmole) of ethyl2,6-dimethyl-4-tert-butyldimethysilyloxy phenoxy acetate in 10 ml ofmethanol was added 4 ml of 3N sodium hydroxide. After the reactionmixture was stirred at room temperature for 30 minutes it was acidifiedwith 3N HCl. The reaction was allowed to stir for additional 1 h, andthen partitioned between water and methylene chloride. The combinedorganic extracts were washed with brine and dried over anhydrous sodiumsulfate, filtered, and evaporated to dryness under reduced pressure.Trituration with hexanes gave 910 mg (77%) of 2,6-dimethyl-4-hydroxylphenoxyacetic acid as a white solid. 300 MHz ¹ H NMR (CD₃ OD) δ2.18 (s,6H), 4.31 (s, 2H), 6.41 (s, 2H). Mass spectrum: (M+H)⁺ =214.

D.(2S,3S,5S)-2-(2,6-Dimethyl-4-hydroxy-phenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 21C with the amine fromExample 1F using standard coupling procedure (EDAC/DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.40 (s, 9H), 1.68 (m, 2H),2.07 (s, 6H), 2.77 (d, J=6 Hz, 2H), 2.98 (m, 2H), 3.74 (m, 1H), 3.90 (m,1H), 4.10 (m, 3H), 4.58 (m, 1H), 5.20 (m, 1H), 6.44 (s, 2H), 7.10-7.30(m, 10H).

E.(2S,3S,5S)-2-(2,6-Dimethyl-4-hydroxy-phenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Removal of the Boc-protecting group of the compound from Example 21Dusing TFA/CH₂ Cl₂ and coupling of the resulting amine with thecarboxylic acid from Example 2A using standard procedure (EDAC/DMF)provided the desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.78 (d, J=5 Hz,3H), 0.81 (d, J=5 Hz, 3H), 1.47 (m, 1H), 2.03 (s, 6H), 2.18 (m, 1H),2.62 (m, 1H), 2.80 (m, 2H), 3.05 (m, 6H), 3.78 (m, 1H), 4.12 (M, 6H),4.37 (M, 1H), 4.71 (s, 1H), 6.47 (s, 6.94 (br d, 1H), 7.20 (m, 10H).Mass spectrum: (M+H)⁺ =645.

EXAMPLE 22(2S,3S,5S)-2-(cis(±)-1,1-dioxo-2-isopropyl-3-tetrahydrothiophenoxy)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

A. Cis(±)-2-isopropyl-3-hydroxy-tetrahydrothiophene

To a solution of ethyl-3-mercaptopropionate (27.25 ml, 0.246 mole) in200 ml of ethanol was added carefully sodium ethoxide (16.75 g, 0.246mole) in several portions. The resulting suspension was then cooled to-20° C. and ethyl-2-bromoisovalerate (50 g, 0.239 mole) in 50 ml ofethanol was added dropwise over 2 h. After addition was complete, thereaction was warmed to ambient temperature and stirred for 3 h. Themixture was poured into 600 ml of ethyl acetate and 600 ml of saturatedNH₄ Cl. The ethyl acetate layer was removed and the aqueous layerextracted (2×200 ml) with ethyl acetate. The combined organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo to give anorange oil. The oil was dissolved in 500 ml of toluene and sodiumethoxide (16.75 g, 0.246 mole) was added. The reaction mixture washeated to reflux for 6 h, cooled to RT, and then poured into an ice-coldsolution of 1N HCl (235 ml) and extracted with ethyl acetate (3×150 ml).The combined organic layers were dried over sodium sulfate, filtered andconcentrated to an oil that was used in the next step withoutpurification.

The crude product was added to 500 ml of aqueous 10% sulfuric acid andthe resulting mixture heated to reflux for several hours, and thencooled to RT and neutralized with 6N sodium hydroxide and extracted withethyl acetate (3×300 ml). The combined organic layer was dried, filteredand concentrated in vacuo to give a dark burgundy oil. The crude product(ketone) was purified by vacuum distillation at 75°-80° C. 300 MHz ¹ HNMR (CDCl₃) δ0.93 (d, J=9 Hz, 3H), 1.03 (d, J=9 Hz, 3H), 2.32 (m, 1H),2.55-2.70 (m, 2H), 2.93 (t, J=7.5 Hz, 2H), 3.38 (d, J=4 Hz, 1H). Massspectrum: (M+H)⁺ =145.

To a stirred solution of the above ketone in 125 ml of CH₂ Cl₂ at 0° C.was added diisobutylaluminum hydride (86 ml, 1M in THF) dropwise over 20minutes. The reaction mixture was allowed to warm to room temperatureand then was quenched by cautious addition of 1N HCl (255 ml). Thereaction mixture was extracted with ether (3×150 ml) and the combinedether solution was washed with satd. sodium bicarbonate, brine and driedover magnesium sulfate. The solution was concentrated in vacuo and theresulting oil was purified by silica gel column chromatography (10%EtOAc/hexane). 300 MHz ¹ H NMR (CDCl₃) δ1.03 (d, J=7 Hz, 3H), 1.08 (d,J=7 Hz, 3H), 1.80 (d, J=9 Hz, 1H), 1.90 (m, 2H), 2.24 (m, 1H), 2.90-3.10(m, 3H), 4.36 (m, 1H). Mass spectrum: (M+H)⁺ =147.

B. Cis(±)-(2-isopropyl-3-thiophenyl)-2(2-pyridyl)carbonate

To the product from Example 22A (2.29 g, 15.7 mmole) in 40 ml of CH₂ Cl₂was added diisopropylethyl amine (4.65 ml, 26.7 mmole) anddi-(2-pyridyl)carbonate (5.42 g, 25.1 mmole). After 18 h at RT, thereaction mixture was diluted with chloroform and washed sequentiallywith 10% citric acid, satd. sodium bicarbonate, brine and then driedover sodium sulfate; filtered and concentrated in vacuo. Purification ofthe crude product by silica gel column chromatography (20% EtOAc/hexane)provided the desired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.05 (d, J=7 Hz,3H), 1.08 (d, J=7 Hz, 3H), 1.90 (m, 1H), 2.05 (m, 2H), 2.58 (dd, J=6, 15Hz, 2H), 3.10 (m, 2H), 3.28 (dd, J=3, 12 Hz, 1H), 5.47 (m, 1H), 7.12 (m,1H), 7.27 (m, 1H), 7.80 (m, 1H), 8.41 (m, 1H). Mass spectrum: (M+H)⁺=268.

C.(2S,3S,5S)-2-(cis(±)-2-isopropyl-3-tetrahydrothiophenoxy)amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

To a solution of the compound from Example 22B (500 mg, 1.87 mmole) in 5ml of CH₂ Cl₂ was added the amine from Example 1F (791 mg, 2.06 mmole).The reaction was stirred at RT until all the compound from Example 22Bwas consumed. The reaction mixture was diluted with chloroform andwashed with 10% citric acid, satd. sodium bicarbonate, brine and thendried with sodium sulfate; filtered and concentrated in vacuo.Purification of the crude product by silica gel column chromatography(2% MeOH/CH₂ Cl₂) provided the desired compound (73%). 300 MHz ¹ H NMR(CDCl₃) δ0.83-1.05 (m, 6H), 1.40 (s, 9H), 1.90 (m, 3H), 2.20 (m, 1H),2.75 (m, 2H), 2.85 (m, 4H), 2.95-3.15 (m, 3H), 3.67-3.90 (m, 4H), 4.55(m, 1H), 5.10 (m, 1H), 5.30 (m, 1H), 7.10-7.26 (m, 10H). Mass spectrum:(M+H)⁺ =557.

D.(2S,3S,5S)-2-(cis(±)-1,1-Dioxo-2-isopropyl-3-tetrahydrothiophenoxy)amino-3-hydroxy-5-(t-butyloxycarbonyl)amino-1,6-diphenylhexane

To the compound from Example 22C (523 mg, 0.91 mmole) in 10 ml ofacetone and 0.5 ml of water was added Oxone (839 mg, 1.37 mmole) andsodium bicarbonate (152 mg, 1.82 mmole). The resulting solution wasstirred for 2 h, at which time a white precipitate appeared. Thereaction was quenched with aqueous sodium bisulfite and extracted withethyl acetate (2×100 ml), dried with sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (2% MeOH/CH₂ Cl₂) to provide 422 mg of product.300 MHz ¹ H NMR (CDCl₃) δ1.20 (m, 6H), 1.40 (s, 9H), 1.60 (m, 4H),2.10-2.32 (m, 4H), 2.67 (m, 2H), 2.75 (m, 2H), 2.85 (m, 2H), 3.15 (m,2H), 3.70-3.90 (m, 3H), 4.56 (m, 1H), 5.30 (m, 2H), 7.10-7.30 (m, 10H).

E.(2S,3S,5S)-2-(cis(±)-1,1-Dioxo-2-isopropyl-3-tetrahydrothiophenoxy)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane

Removal of the Boc-protecting group of the compound from Example 22Dusing TFA/CH₂ Cl₂ and coupling of the resulting amine with thecarboxylic acid from Example 2A provided the desired compound (82%). 300MHz ¹ H NMR (CDCl₃) δ0.82 (m, 6H), 1.0-1.20 (m, 6H), 1.60 (, 2H), 2.07(m, 1H), 2.25 (m, 2H), 2.65-3.20 (m, 12H), 3.70 (m, 1H), 3.90 (m, 1H),4.10-4.20 (m, 2H), 5.07 (m, 1H), 5.37 (m, 1H), 5.87-5.98 (m, 1H),6.95-7.05 (m, 1H), 7.20 (m, 10H). Mass spectrum: (M+H)⁺ =671.

EXAMPLE 23(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-dihydropyrimid-2,4-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

A. N-(2-Ethoxyacryloyl)-N'-(1S-carbomethoxy-2-methyl-propyl)-urea

To 1.74 g (0.013 mole) of 2-ethoxy-acryloyl chloride in 18 ml of toluenewas added 3.90 g (0.026 mole) of silver cyanate. The mixture was heatedto reflux for 0.75 h. The mixture was allowed to cool to RT and theprecipitate allowed to settle. The supernatant (9.6 ml) was withdrawnand added to 18 ml of dry DMF and 5 ml of Et₂ O, cooled to -15° C. for45 minutes and left in freezer overnight. The solvent was evaporated invacuo and the residue was purified by silica gel column chromatography(2% MeOH/CH₂ Cl₂) to provide 1.59 g of desired compound (90.2%). 300 MHz¹ H NMR (CDCl₃) δ0.96 (d, J=7 Hz, 3H), 1.0 (d, J=7 Hz, 3H), 1.37 (t,J=7.5 Hz, 3H), 2.25 (m, 1H), 3.74 (s, 3H), 3.97 (q, J=7.5 Hz, 2H), 4.42(dd, J=4.5, 8.0 Hz, 1H), 5.25 (d, J=12 Hz, 1H), 7.68 (d, J=12 Hz, 1H),8.55 (s, 1H), 9.10 (d, J=8 Hz, 1H). Mass spectrum: (M+H)⁺ =273.

B. 2S-(1-Dihydropyrimid-2,4-dionyl)-3-methyl butanoic acid

A solution of 174 mg (0.64 mmole) of the compound from Example 23A in 10ml of 2N sulfuric acid was refluxed for 2 h, cooled to RT and left infreezer overnight. The mixture was concentrated and the residue wasextracted with ethyl acetate (2×100 ml), dried and concentrated in vacuoto give 122 mg of desired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.06 (d,J=7 Hz, 3H),1.13 (d, J=7 Hz, 3H), 2.25 (m, 1H), 5.04 (d, J=10 Hz, 1H),5.74 (d, J=7 Hz, 1H), 7.50 (d, J=10 Hz, 1H), 8.43 (s, 1H).

C.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-dihydropyrimid-2,4-dionyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane

Coupling of the carboxylic acid from Example 23B with the amine fromExample 1N using standard coupling procedure (EDAC in DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.81 (d, J=7 Hz, 3H), 0.92(d, J=7 Hz, 3H), 2.18 (s, 6H), 2.23 (m, 1H), 2.63 (m, 1H), 2.85 (m, 1H),3.0 (m, 2H), 3.78 (m, 1H), 4.20 (m, 4H), 4.58 (d, J=10 Hz, 1H), 5.68(dd, J=1.5, 7.5 Hz, 1H), 7.0-7.25 (m, 13H), 7.50 (d, J=7.5 Hz, 1H), 9.50(s, 1H). Mass spectrum: (M+H)⁺ =640.

EXAMPLE 24 Alternate Preparation of(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. 2,6-Dimethylphenoxyacetic acid

2,6-Dimethylphenol (102.8 g, 0.842 mol) and chloroacetic acid (159.6 g,1.68 mol) in 1000 ml of H₂ O was added to a 3-L, 3-necked round bottomflask with mechanical stirring and a water-cooled condenser. A solutionof NaOH (134.9 g, 3.37 mol) dissolved in 500 ml of water was slowlyadded to the above mixture via addition funnel and heat to reflux. After2 hours, additional chloroacetic acid (79.4 g, 0.84 mol) and NaOHsolution (67.2 g, 1.68 mol in in 200 ml water) was added to the reactionmixture. After 19 hours, additional chloroacetic acid (39.8 g, 0.42 mol)and NaOH solution (33.6 g, 0.84 mol in in 100 ml water) was added to thereaction mixture and refluxing was continued until starting phenol wasconsumed. The reaction flask was cooled in and ice-water bath andacidified to pH=1 with conc. HCl, causing a precipitate to form. Theresulting slurry was stirred in the ice bath for 1 hour then filtered.The solid was dissolved in hot (100° C.) water and cooled to crystallizethe product as white plates, mp=136-137° C., yield=78.8 g, 52%.

B.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane

Oxallyl chloride (36.3 ml, 0.42 mol) was added to a slurry of 2-6dimethylphenoxyacetic acid (50 g, 0.28 mol) in 500 ml toluene followedby addition of 5 drops of DMF and stirred at room temperature for 30min, then at 55° C. for 1.5 hours. The toluene was removed on a rotaryevaporator and remaining volatiles were removed in vacuo to afford2,6-dimethylphenoxyacetyl chloride as an amber oil, 55 grams, 100%.

2S,3S,5S!-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-diphenylhexane.times.0.5succinate (111.9 g, 0.25 mol) was charged to a 2L, 3-neckedround-bottomed flask with mechanical stirring. NaHCO₃ (106 g, 1.26 mol),600 ml H₂ O and 600 ml EtOAc were added and stirred vigorously until allsolids were dissolved (15 minutes). Stirring was slowed and a solutionof the 2,6-dimethyl-phenoxyacetyl chloride and EtOAc (100 ml) was addedin a narrow stream via addition funnel. After 30 min of stirring,starting materials were consumed (HPLC analysis) and the layers wereseparated. The aqueous layer was extracted with EtOAc, the organiclayers were combined and washed with 200 ml of 1M NaOH, 200 ml of 10%HCl, 200 ml of brine, dried over MgSO₄, filtered and concentrated toprovide the desired product as a white solid.

C.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane

(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane(175.1 g, 0.32 mol) and 500 ml CH₂ Cl₂ were mixed with stirring. CF₃ CO₂H (249 ml, 3.2 mol) was added and stirred 20-25 minutes, then thereaction mixture was poured into a separatory funnel containing 1000 mlof water and 200 ml of CH₂ Cl₂. The resulting mixture was shakencarefully and the layers were separated. The organic layer was washedagain with 500 ml of water, then 3×500 ml of NaHCO₃ and finally 500 mlof brine. The organic solution was dried over MgSO₄, filtered andconcentrated to a golden oil that pulled into a foam 300 ml of diethylether was added to the crude product and shaken vigorously to dissolve.Within minutes solid began to crystallize and the mixture became thick.Enough diethyl ether was added to make the mixture stirrable and themixture was stirred at room temperature for 1 hour. The solid wasfiltered and air dried to give the desired product as 115 g of whiteneedles, 81% yield.

A solution of HCl/diethyl ether was added to the filtrate to precipitatethe remaining product as the HCl salt. This pinkish solid was collectedby filtration, taking care to keep the solid flooded with N₂ while itwas wet with ether. When dry, transfered the amine salt to a separatoryfunnel and extracted with CH₂ Cl₂ and NaHCO₃ (aq). The organic layer waswashed with brine, dried over MgSO₄, concentrated and treated as aboveto afford an additional 15 g of the desired product, the total yield is91%.

D. N-Carbonylbenzyloxy-3-aminopropanol

To a 12 L 3-neck round bottom flask was added isopropyl acetate (6.5 L).The solvent was cooled to 0° C. in an ice-water bath and3-amino-1-propanol (1.14 Kg, 15.1 mol, 2.15 eq) was added in oneportion. To this rapidly stirring solution, benzyl chloroformate (1.20Kg, 7.03 mol, 1.0 eq) was added dropwise over 2 h while maintaining theinternal temperature of the flask between 10° C. and 15° C. After theaddition was complete, the reaction mixture was allowed to stir between10° C. and 15° C. for an additional 0.3 h after which time water (3.5 L)was added in one portion. The solution was then partitioned and washedwith an additional 2×3.5 L of water. The organic layer was dried overpotassium carbonate and concentrated to give a solid that was dissolvedin excess isopropyl acetate and precipitated from solution by adding thecompound to heptane. The solid was filtered under nitrogen to yield 1.20Kg (82%) of the desired product as a colorless solid.

E. N-Carbonylbenzyloxy-3-aminopropanal

335 mL of dimethylsulfoxide and 9 L of methylene chloride were combinedand chilled to -48° C. 313 mL of oxalyl chloride was added over 25minutes so that the temperature remained below -40° C. Cooled to -48°C., and added 500 grams of N-Cbz-3-amino-1-propanol dissolved in 1 L ofmethylene chloride so that the temperature remained below -40° C.Stirred for an additional hour at -45° C. 1325 mL of triethylamine wasadded at such a rate that the temperature remained below -40° C. Afterstirring an additional 15 minutes at -40° C., the mixture was allowed towarm to -30° C., then added 2.5 L of 20% aqueous potassium dihydrogenphosphate. Stirred for one hour, then separated the layers, washed theorganic layer with brine, and dried with magnesium sulfate. Theresulting aldehyde was kept in solution at -20° C. until needed.

F. N-(N-(Benzyloxycarbonyl-3-amino)-propyl)valine methyl ester

To a 5 L 3-neck round bottom flask was added the crude(unchromatographed) product of Example 24E (115 g, 0.555 mol, 1.0 eq)followed by addition of water (400 mL) and methanol (1600 mL). Thereaction mixture was maintained at 25° C. throughout the course of thereaction. After the solution became homogeneous, (S)-Valine methyl esterhydrochloride (90.2 g, 0.538 mol, 0.97 eq) was added in one portionfollowed by rapid addition of sodium acetate trihydrate (151 g, 1.11mol, 2.0 eq) and sodium cycanoborohydride (73.2 g, 1.17 mol, 2.1 eq) insaid order. The reaction mixture was allowed to stir at room temperaturefor 0.5 h and was concentrated in vacuo to remove all methanol present.To this solution, saturated aq sodium bicarbonate (400 mL) was added andthe mixture was extracted with isopropyl acetate (1 L). The organiclayer was washed with water (2×400 mL), dried over sodium sulfate, andconcentrated to yield 150 g of crude product, which was dissolved inisopropyl acetate (300 mL) and heptane (2400 mL). Dry HCl was bubbled inand an oily solid precipitated out of solution. The liquid was decantedaway from the solid and was dissolved in dichloromethane (3 L). Thesolution was washed with water (600 mL) and saturated aq sodiumbicarbonate (600 mL) and dried over sodium sulfate. It was concentratedin vacuo to yield 105 g (59%) of the desired product as a light yellowoil.

G. N-(3-amino)-propyl)valine methyl ester

To a 3 L flask was added the product of Example 24F (120 g, 0.372 mol)and methanol (1 L). This solution was allowed to stir in the presence ofRaney Nickel (180 g) for 1 h. After removal of Raney Nickel byfiltration, Pd(OH)₂ (24 g) was added and the solution was allowed tostir under 60 psi of a hydrogen atmosphere for 12 h. The solution waspurged with nitrogen and repressurized with 60 psi of hydrogen for anadditional 1 h. The solution was filtered and concentrated to give 63 gof an oil (90%). To this oil toluene (120 mL) was added and the solutionwas again concentrated in vacuo to give the desired product.

H. 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid methyl ester

To a 5 L 3-neck round bottom flask with stir bar was added the crudeproduct of Example 24G (150 g, 0.8 mol) and dichloromethane (3.2 L).Carbonyldiimidazole (232 g, 1.44 mol, 1.8 eq) was added slowly inportions over 25 min. The solution was allowed to stir at ambienttemperature for 40 h. Water (200 mL) was added over 1 h with carefulstirring until no more gas evolution occurred. A solution of 35% HCl wasslowly added to the stirring solution until the solution became acidic.The solution was then partitioned and was washed with water (2×300 mL).The organic layer was dried over sodium sulfate and was concentrated toyield 126 g (74%) of the desired product as a colorless solid.

I. 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid methyl ester

To a 12 L 3-neck round bottom flask with stir bar was added the productof Example 24H (126 g, 0.588 mol), water (1.3 L), and THF (3.9 L). Thesolution was cooled to 0° C. in an ice-water bath and lithium hydroxidemonohydrate (74 g, 1.76 mol, 3.0 eq) was added in one portion with rapidstirring. The solution was allowed to stir at 0° C. for 14 h. It wasthen acidified to pH 11 by slow addition of 50% aq phosphoric acid andthe THF was removed in vacuo. The aqueous phase was washed withisopropyl acetate (2 L) and was subsequently acidified to pH by slowaddition of 35% aq HCl. The aqueous layer was then extracted with ethylacetate (5×2.2 L). The combined organic layers were concentrated to givethe desired product (105 g) as a white solid. The compound was thenpurified by addition of isopropyl acetate (500 mL) and ethanol (15 mL)and bringing the solution to a boil with rapid stirring until 50 mL ofsolvent had evaporated. The solution was cooled to 0° C. and filered togive 92 g (75%) of pure desired product.

J. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

In a 2 L, 3-necked round-bottomed flask were combined the product ofExample 24C (100 g, 0.22 mol), the product of Example 241 (44.8 g, 0.22mol) and 750 ml DMF and the mixture was cooled in an ice/water bath.HOBT (90.9 g, 0.67 mol), EDAC (86 g, 0.45 mol) and triethylamine (62.5ml, 0.45 mol) were added and the ice bath was removed, allowing thereaction mixture to stir with warming to room temperature for 5 h. Thereaction was diluted with 1000 ml of IPAC and quenched with 1000 ml ofwater. The mixture was shaken and separated, the aq. layer was extracted1×400 ml IPAC, the organics were washed with 1×400 ml 10% HCl, 1×500 mlNaHCO₃, diluted with 100 ml hexanes, then washed 4×500 ml water, and1×500 ml brine, dried over MgSO₄, filtered and concentrated to providethe desired product as a white foam.

EXAMPLE 25 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. N-(2-Carbomethoxy)ethyl-L-Valine t-butyl ester

To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanolwas added 9.0 ml of methyl acrylate. The solution was heated to refluxovernight. Another 9.0 ml of methyl acrylate was added and continued thereflux for 24 h. The solvent was evaporated in vacuo and the crudeproduct was purified by silica gel column chromatography (20% ethylacetate in hexane) to provide 2.435 g of desired compound (93.9%). 300MHz ¹ H NMR (CDCl₃) δ0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H),1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d,J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)⁺ =260.

B. N-(2-Carboxamido)ethyl-L-Valine t-butyl ester

To a solution of 1.86 g of the product from Example 25A in 5 ml of THFwas added 0.415 g of lithium hydroxide monohydrate in 10.8 ml of water.After 40 min, 10.8 ml of 1N HCl was added. The reaction mixture wasevaporated to dryness and dry pyridine was added and evaporated todryness two times. The residue was dissolved in 25 ml of acetonitrileand 0.62 ml of dry pyridine added. To this solution was added 2.02 g ofN,N'-disuccinimidyl carbonate. The reaction mixture was stirred for 3.5h. The solvent was removed in vacuo and 90 ml of THF added followed by1.43 ml of conc. ammonium hydroxide. The reaction was allowed to goovernight. The reaction mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in ethyl acetate andwashed with sodium bicarbonate, brine and dried with anhy. sodiumsulfate. After filtering off the drying agent, the filtrate was conc. invacuo and the crude product was purified by silica gel columnchromatography (5% MeOH in CH₂ Cl₂) to give 1.19 g (68%) of desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.95 (d, J=7 Hz, 3H), 0.97 (d, J=7Hz, 3H), 1.48 (s, 9H), 1.93 (m, 1H), 2.37 (m, 2H), 2.65 (m, 1H), 2.95(m, 2H), 5.30 (br s, 1H), 7.85 (br s, 1H). Mass spectrum: (M+H)⁺ =245.

C. 2S-(1-Tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoic acid t-butylester

A solution of 0.92 g of the product from Example 25B in 10 ml of THF and1.83 g of carbonyldiimidazole (CDI) was refluxed for 26 h. Then 1.83 gof CDI was again added and the solution was refluxed for 72 h more. Thesolvent was evaporated in vacuo and the residue was dissolved in ethylacetate and washed with water, satd. sodium bicarbonate, dilutehydrochloric acid and then brine. The organic layer was dried, filteredand conc. in vacuo. The crude product was purified by silica gel columnchromatography (2% to 5% MeOH in CH₂ Cl₂) to give 0.54 g (52%) ofdesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.96 (d, J=7 Hz, 3H), 1.05(d, J=7 Hz, 3H), 1.48 (s, 9H), 2.20 (m, 1H), 2.66 (m, 2H), 3.43 (m, 1H),3.75 (m, 1H), 4.63 (d, J=9 Hz, 1H), 7.35 (br s, 1H). Mass spectrum:(M+H)⁺ =271.

D. 2S-(1-Tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoic acid

A solution of 0.53 g of the compound from Example 25C in 5 ml oftrifluoroacetic acid was stirred at 0° C. for 1.25 h. Solvent wasevaporated in vacuo, dried and purified by silica gel columnchromatography (2% MeOH/4% HOAc in CH₂ Cl₂) to give 0.36 g of desiredcompound. 300 MHz ¹ H NMR (DMSO-d₆) δ0.86 (d, J=7 Hz, 3H), 0.97 (d, J=7Hz, 3H), 2.15 (m, 1H), 3.40 (m, 4H), 4.39 (d, J=10 Hz, 1H). Massspectrum: (M+H)⁺ =215.

E. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the acid fromExample 25D using standard coupling procedure (EDAC in DMF) provided thedesired compound (68%). 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, J=7 Hz, 3H),0.88 (d, J=7 Hz, 3H), 1.80 (m, 2H), 2.20 (s, 6H), 2.40 (m, 1H), 2.58 (m,1H), 2.80 (m, 1H), 2.92 (m, 1H), 3.05 (m, 3H), 3.65 (d, J=5 Hz, 1H),3.83 (m, 1H), 4.20 (m, 5H), 6.18 (d, J=9 Hz, 1H), 7.0-7.38 (m, 14H).Mass spectrum: (M+H)⁺ =643.

EXAMPLE 26 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(4-aza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

A. N(1)-t-butyloxycarbonyl-N(2)-allyl hydrazine

To a solution of 18.18 g of t-butyloxycarbonyl protected hydrazine in 50ml of acetonitrile was added 19.0 g of potassium carbonate, followed by11.9 ml of allyl bromide. The reaction mixture was heated at reflux fora total of 3 h, filtered and conc. in vacuo. The residue was dissolvedin ethyl acetate and washed with satd. sodium bicarbonate and dried withanhydrous sodium sulfate and filtered. After concentration in vacuo, thecrude product was purified by silica gel column chromatography (20%EtOAc/hexane) to give 4.47 g of desired compound. 300 MHz ¹ H NMR(CDCl₃) δ1.45 (s, 9H), 3.46 (m, 2H), 4.0 (br s, 1H), 5.10 (m, 2H), 5.83(m, 1H), 6.0 (br s, 1H). Mass spectrum: (M+H)⁺ =173.

B. N(1)-t-butyloxycarbonyl-N(2)-allyl-N(2)-benzyloxycarbonyl hydrazine

To a solution of 4.8 g of the compound from Example 26A in 15 ml of DMFwas added 4.69 g of benzyloxycarbonyloxy-succinimide. The reactionmixture was stirred at RT for 72 h and the solvent was evaporated invacuo. The residue was dissolved in ethyl acetate, washed with satd.sodium bicarbonate and dried with anhydrous sodium sulfate. The crudeproduct obtained after concentration was purified by silica gel columnchromatography (20% to 50% EtOAc in hexane) and provided 5.27 g ofdesired compound. 300 MHz ¹ H NMR (CDCl₃) δ1.43 (br s, 9H), 4.15 (br s,2H), 5.18 (s, 2H), 5.20 (m, 2H), 5.82 (m, 1H), 6.39 (br s, 1H), 7.36 (m,5H). Mass spectrum: (M+H)⁺ =307.

C. N(1)-t-butyloxycarbonyl-N(2)-formylmethyl-N(2)-benzyloxycarbonylhydrazine

A solution of 6.5 g of the compound from Example 26B in 100 ml ofmethanol was cooled with a dry ice/acetone bath. Ozone was bubbled infor 1.75 h until a pale blue color persisted. Air was passed through thesolution for 10 min and then 15.6 ml of dimethyl sulfide was added andthe reaction mixture was allowed to warm gradually to RT overnight.Solvent was evaporated in vacuo and the residue was dissolved in ethylacetate and washed with water, then brine several times. The organiclayer was dried with anhydrous sodium sulfate, filtered and conc. invacuo to provide 7.2 g of the desired compound. 300 MHz ¹ H NMR (CDCl₃)δ1.40 (br s, 9H), 4.35 (m, 2H), 5.20 (s, 2H), 6.65 (br s, 1H), 7.36 (s,5H), 9.70 (br s, 1H). Mass spectrum: (M+NH₄)⁺ =326.

D. N-2-(N-(2)-benxyloxycarbonyl-N-(1)-t-butyloxycarbonylhydrazinyl!ethyl-L-Valinemethyl ester

To a solution of 7.2 g of the compound from Example 26C in 100 ml ofmethanol was added 3.55 g of L-valine methyl ester hydrochloride,followed by 3.48 g of sodium acetate and 1.33 g of sodiumcyanoborohydride. The reaction mixture was stirred at RT overnight. Themixture was filtered and concentrated in vacuo. The crude product waspurified by silica gel column chromatography (2% MeOH in CH₂ Cl₂) toprovide 5.8 g of desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.90 (d, J=6Hz, 6H), 1.43 (br s, 9H), 1.87 (m, 1H), 2.60-3.0 (m, 4H), 3.72 (s, 3H),5.18 (s, 2H), 7.37 (m, 5H). Mass spectrum: (M+H)⁺ =424.

E. 2S-4-benzyloxycarbonylaza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoicacidmethyl ester

A solution of 2.4 g of the compound from Example 26D in 20 ml of HCl indioxane was stirred at RT under argon for 1 h. Solvent was evaporated invacuo and the residue was washed with satd. sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried, filtered andconcentrated in vacuo. The crude product was dissolved in 28 ml of CH₂Cl₂ and 0.56 g of carbonyldiimidazole was added. The solution was leftat RT for 48 h. The solvent was removed and the residue was purified bysilica gel column chromatography (10% to 30% EtOAc in CH₂ Cl₂) to give0.78 g of desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.90 (d, J=7 Hz,3H), 0.98 (d, J=7 Hz, 3H), 2.17 (m, 1H), 3.34 (m, 1H), 3.61 (m, 2H),3.72 (s, 3H), 3.98 (m, 1H), 4.71 (d, J=10 Hz, 1H), 5.20 (s, 2H), 6.72(br s, 1H), 7.38 (m, 5H). Mass spectrum: (M+H)⁺ =350.

F.2S-(4-Benzyloxycarbonylaza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanoicacid

Hydrolysis of 0.78 g of the compound from Example 26E using lithiumhydroxide in aqueous dioxane provided 0.35 g of desired compound. 300MHz ¹ H NMR (CDCl₃) δ0.85 (d, J=7 Hz, 3H), 1.04 (d, J=7 Hz, 3H), 2.40(m, 1H), 3.40 (m, 1H), 3.50 (m, 1H), 3.80 (m, 2H), 3.95 (d, J=10 Hz,1H), 5.20 (s, 2H), 7.30 (s, 1H), 7.36 (s, 5H). Mass spectrum: (M+H)⁺=336.

G. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(benzyloxycarbonylaza-1-tetrahydro-pyrimid-2-onyl)-3-methyl-butanyl!amino-1,6-diphenylhexane

Coupling of the amino compound from Example 1N with the acid fromExample 26F using standard coupling procedure (EDAC/DMF) provided thedesired compound (36%). 300 MHz ¹ H NMR (CDCl₃) δ0.72 (d, J=7 Hz, 3H),0.83 (d, J=7 Hz, 3H), 2.20 (s, 6H), 2.65 (m, 1H), 2.83 (m, 1H), 3.0-3.10(m, 4H), 3.90 (m, 1H), 6.65 (m, 1H), 7.0-7.35 (m, 18H). Mass spectrum:(M+H)⁺ =764.

H. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(4-aza-1-tetrahydro-pyrimid-2-oxyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

Removal of the benzyloxycarbonyl protecting group of the compound fromExample 26G by hydrogenolysis using 10% palladium on carbon as catalystprovided the desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, J=4.5Hz, 3H), 0.86 (d, J=4.5 Hz, 3H), 1.80 (m, 1H), 2.20 (s, 6H), 2.58 (m,1H), 2.67 (m, 1H), 2.90 (m, 2H), 3.0 (m, 2H), 3.80 (m, 1H), 4.20 (m,3H), 6.72 (m, 1H), 7.0 (m, 2H), 7.20 (m, 11H). Mass spectrum: (M+H)⁺=630.

EXAMPLE 27 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1-phenyl-6-methylheptane

A.(2S,3S,5S)-2-Amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1-phenyl-6-methylheptane

Following the procedures described in Example 1A to Example 1F-1, butsubstituting isopropylmagnesium chloride for benzylmagnesium chloride inExample 1C provided the desired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.88(d, J=7 Hz, 3H), 0.92 (d, J=7 Hz, 3H), 1.43 (s, 9H), 1.50-1.80 (m, 4H),2.55 (m, 1H), 2.90 (m, 1H), 3.0 (m, 1H), 3.54 (m, 2H), 4.62 (m, 1H),7.30 (m, 5H), Mass spectrum: (M+H)⁺ =337.

B.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1-phenyl-6-methylheptane

Coupling of the amino compound from Example 27A with the acid fromExample 1H using standard EDAC coupling procedure provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.85 (d, J=7 Hz, 3H), 0.90 (d, J=7Hz, 3H), 1.43 (s, 9H), 1.70 (m, 2H), 2.20 (s, 6H), 3.03 (d, J=8 Hz, 2H),3.42 (m, 1H), 3.80 (m, 1H), 4.20 (m, 2H), 4.22 (s, 2H), 4.55 (m, 1H),7.0 (m, 3H), 7.30 (m, 5H). Mass spectrum: (M+H)⁺ =499.

C.(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1-phenyl-6-methylheptane

Removal of the t-butyloxycarbonyl protecting group of the compound fromExample 27B using the procedure of Example 1N provided the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.90 (d, J=3 Hz, 3H), 0.94 (d, J=3Hz, 3H), 1.60 (m, 4H), 2.20 (s, 6H), 2.85 (m, 2H), 3.0 (m, 1H), 3.85 (m,1H), 4.20 (m, 2H), 7.0 (m, 2H), 7.35 (m, 6H). Mass spectrum: (M+H)⁺=399.

D. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S,(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1-phenyl-6-methylheptane

Coupling of the amino compound from Example 27C with the acid fromExample 2A using standard coupling procedure (EDAC/DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.88 (m, 12H), 1.67 (m, 2H),1.90 (m, 1H), 2.20 (s, 6H), 3.0 (d, J=8 Hz, 2H), 3.22 (m, 4H), 3.67 (m,1H), 3.77 (m, 1H), 4.20 (s, 2H), 4.40 (m, 1H), 4.76 (m, 1H), 7.0 (m,3H), 7.30 (m, 5H). Mass spectrum: (M+H)⁺ =581.

EXAMPLE 28 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2,4-dionyl)-3-methylbutanoyl!amino-1-phenyl-6-methylheptane

Coupling of the amino compound from Example 27C with the acid fromExample 25D using standard coupling procedure (EDAC/DMF) provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.83 (d, J=7 Hz, 6H), 0.92(t, J=7 Hz, 6H), 1.73 (m, 2H), 2.18 (s, 6H), 2.30 (m, 1H), 2.62 (m, 2H),3.03 (m, 2H), 3.45 (m, 1H), 3.55 (m, 1H), 4.72 (m, 2H), 4.20 (m, 4H),6.40 (br d, J=9 Hz, 1H), 7.0 (m, 3H), 7.30 (m, 5H), 7.62 (br s, 1H).Mass spectrum: (M+H)⁺ =595.

EXAMPLE 29 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-piperazin-2,3-dionyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. 2S-(4-benzyloxycarbonyl-1-piperazin-2,3-dionyl)-3-methylbutanoic acidmethyl ester

To a solution of 0.77 g of N-(benzyloxycarbonylamino)-ethyl-L-Valinemethyl ester in 20 ml of toluene and 10 ml of acetonitrile was added0.79 g of oxalyl diimidazole. The reaction mixture was kept at 50° C.for 24 h and 0.2 g of oxalyl diimidazole was added. The reaction mixturewas kept at 50° C. for another 72 h. Evaporation of solvent in vacuo andpurification of the crude product by silica gel column chromatography(10% EtOAc in CH₂ Cl₂) provided the desired compound. 300 MHz ¹ H NMR(CDCl₃) δ0.95 (d, J=7 Hz, 3H), 1.03 (d, J=7 Hz, 3H), 2.20 (m, 1H), 3.60(m, 1H), 3.73 (s, 3H), 3.85 (m, 1H), 4.0 (m, 1H), 4.10 (m, 1H), 4.90 (d,J=10 Hz, 1H), 5.36 (s, 2H), 7.20 (m, 5H). Mass spectrum: (M+NH₄)⁺ =380.

B. 2S-(1-piperazin-2,3-dionyl)-3-methylbutanoic acid methyl ester

Removal of the benzyloxycarbonyl protecting group of the compound fromExample 29A by hydrogenolysis using 10% Pd/C as catalyst provided thedesired compound. 300 MHz ¹ H NMR (CDCl₃) δ0.95 (d, J=7 Hz, 3H), 1.03(d, J=7 Hz, 3H), 2.20 (m, 1H), 3.50 (m, 3H), 3.74 (s, 3H), 3.83 (m, 1H),5.0 (d, J=10 Jz, 1H), 7.30 (br s, 1H). Mass spectrum: (M+H)⁺ =229.

C. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(1-piperazin-2,3-dionyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

The methyl ester from Example 29B was hydrolyzed using the procedure ofExample 1M and the resulting acid was coupled to the amino compound fromExample 1N using standard EDAC coupling procedure to provide the desiredcompound. 300 MHz ¹ H NMR (CDCl₃) δ0.82 (d, J=6 Hz, 3H), 0.85 (d, J=6Hz, 3H), 1.80 (m, 2H), 2.18 (m, 1H), 2.20 (s, 6H), 2.65 (m, 1H),2.82-3.0 (m, 4H), 3.30 (m, 3H), 3.70 (m, 1H), 3.82 (m, 1H), 4.22 (m,3H), 4.54 (d, J=10 Hz, 1H), 6.30 (br s, 1H), 6.65 (br d, 1H), 7.0-7.30(m, 13H). Mass spectrum: (M+H)⁺ =643.

EXAMPLE 30 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(4-aza-4,5-dehydro-1-pyrimid-2-onyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

A. 2S-(4-Aza-4,5-dehydro-1-pyrimid-2-onyl)-3-methyl-butanoic acid

From the hydroysis product mixture of Example 26F, the desired productwas isolated after column chromatography (5% MeOH/5% AcOH in CH₂ Cl₂) in12.5% yield. 300 MHz ¹ H NMR (CD₃ OD) δ0.93 (d, J=7 Hz, 3H), 1.04 (d,J=7 Hz, 3H), 2.20 (m, 1H), 3.92 (dd, J=15, 3 Hz,, 1H), 4.09 (dd, J=15, 3Hz, 1H), 4.50 (d, J=10 Hz, 1H), 6.95 (t, J=3 Hz, 1H). Mass spectrum:(M+H)⁺ =334.

B. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-52S-(4-aza-4,5-dehydro-1-pyrimid-2-oxyl)-3-methyl-butanoyl!amino-1,6-diphenylhexane

Coupling of the compound from Example 1N with the acid from Example 30Ausing standard coupling procedure (EDAC/DMF) provided the desiredcompound (70%). 300 MHz ¹ H NMR (CDCl₃) δ0.80 (d, J=7 Hz, 3H), 0.85 (d,J=7 Hz, 3H), 1.75 (m, 2H), 2.15 (m, 1H), 2.20 (s, 6H), 2.62 (m, 1H),2.85 (m, 1H), 3.02 (m, 2H), 3.55 (m, 2H), 3.80 (m, 1H), 4.20 (m, 4H),6.38 (br d, 1H), 6.72 (t, J=3 Hz, 1H), 7.0 (m, 3H), 7.22 (m, 10H), 7.63(s,1H). Mass spectrum: (M+H)⁺ =628.

EXAMPLE 31 cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-phenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide

The title compound can be prepared by coupling the product of Example 2Awith cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-phenyl-3(S)-aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide(disclosed in PCT Patent Application No. WO9426749 and U.S. Pat. No.5,196,438, issued Mar. 23, 1993, both of which are incorporated hereinby reference) using a standard coupling procedure (EDAC in DMF).

EXAMPLE 32 cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-thiophenyl-3(S)-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide

The title compound can be prepared by coupling the product of Example 2Awith cis-N-tert-butyl-decahydro-2-2(R)-hydroxy-4-thiophenyl-3(S)-aminobutyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide(disclosed in PCT Patent Application No. WO95/09843, published Apr. 13,1995 and U.S. Pat. No. 5,484,926, issued Jan. 16, 1996, both of whichare incorporated herein by reference) using a standard couplingprocedure (EDAC in DMF).

EXAMPLE 334-Amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide

The title compound can be prepared by coupling the product of Example 2Awith4-Amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-amino)-butyl)-N-isobutyl-benzenesulfonamide(disclosed in PCT Patent Application No. WO94/05639, published Mar. 17,1994, which is incorporated herein by reference) using a standardcoupling procedure (EDAC in DMF).

EXAMPLE 34 A. Alternative Preparation of(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane

To a 1 liter 3-necked flask equipped with a mechanical stirrer, J-Kem®temperature probe, dropping addition funnel, and dry nitrogen line wascharged 30.0 g (54.87 mmol) of the product of Example 11 and 120 mL ofacetonitrile. The resultant slurry was cooled to 0-5° C. and 54.1 g (549mmol) of 37% aqueous hydrochloric acid was slowly added, maintaining aninternal temperature of not more than +5° C. during the addition. Thereaction mixture was stirred at 0-5° C. and samples were takenperiodically to analyze for consumption of starting material by HPLC(Zorbax C-8 column, mobile phase=1:1 acetonitile/0.1% aqueous phosphoricacid, flow rate=1.5 mL/minute, detection at 205 nm).

After stirring for 3 hours the reaction was complete. The reaction wasquenched by the slow addition of 105 mL of 20% aqueous sodium hydroxide,again maintaining an internal temperature of not more than +5° C. duringthe addition. Once the pH of the reaction mixture was confirmed to bebasic, the solution was warmed to room temperature. Ethyl acetate (180mL) was added with mixing and, after settling, the lower aqueous phasewas separated and discarded. The organic phase was then washed once with105 mL of 10% aqueous sodium chloride.

The title compound was crystallized from 12 mL/g of 1:2 ethylacetate/heptane (yield 80-85%).

B. Alternative Preparation of(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-amino-1,6-diphenylhexane

To a round-bottom 3-neck 1 L flask with attached mechanical stirbar andthermometer was added the product of Example 11 (51.6 g, 0.095 mol) and100 mL of glacial acetic acid. To the resulting suspension was added 35%aqueous HCl (10.5 mL, 0.103 mol) in 1 portion. The solution was allowedto stir under a N₂ atmosphere for 3 h, at which time an additional 10.5mL of 35% aqueous HCl was added. After an additional 1.5 h, the reactionflask was immersed in an ice bath and a NaOH solution (16 mL, 0.198 mol)was added at a rate to maintain the internal temperature of the flaskbelow 30° C. Water (200 mL) was added and the mixture extracted with4×200 mL of Isopropyl Acetate. The combined organic layers were washedwith 2.5M NaOH (2×200 mL), 100 mL H₂ O, brine, dried over Na₂ SO₄,filtered and evaporated in vacuo to yield 39.7 g (94% crude) of productas a colorless solid in greater than 95% purity by HPLC. The productcould be further purified by dissolving in 200 mL isopropanol heatedover a steam bath, allowed to cool with stirring to 0-5° C. to yield32.2 g (76%) of the desired product, m.p.=131° C.

EXAMPLE 35 Alternative Preparation of2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

A. N-phenoxycarbonyl-L-valine

N-phenoxycarbonyl-L-valine may be prepared according to the proceduresdisclosed in U.S. patent application Ser. No. 08/08/671,893, filed Jun.28, 1996, which is incorporated herein by reference, and which includethe following method.

Into a reactor equipped with an overhead stirrer, chiller, pH probe andthermocouple was added lithium chloride (15.6 kg, 368 moles), L-valine(26.0 kg, 222 moles), neutral alumina (8.1 kg, 150 mesh, Aldrich) and156 kg of distilled water. The heterogeneous mixture was stirred andcooled to -14° C.±5° C. The pH was adjusted to 10.1 with 10% aqueouslithium hydroxide. Precooled (-20° C.) phenylchlorformate (36.6 kg, 234moles) was added while maintaining a temperature of not more than -9° C.and the pH was controlled during the reaction (maintaining a pH withinthe range of 9.5 to 10.5 with a target of 10.0) using a continuousaddition of 10% aqueous lithium hydroxide.

The reaction was stirred for 2 hours at about -14° C. The reactionmixture was filtered through Celite and the filter cake was washed with42 kg of distilled water. The aqueous filtrate was extracted with methylt-butyl ether (65 kg) to remove residual phenol. The aqueous phase wasthen cooled to 0-5° C. and mixed with 200 kg of toluene. The stirredbiphasic solution was adjusted to pH 1.8-2.0 with 25% (w/w) sulfuricacid. The toluene layer was concentrated at not more than 40° C. toapproximately 120 L, filtered (30 kg rinse of toluene) and thenconcentrated again at not more than 40° C. to approximately 120 L.

To the resulting solution was added 44.2 kg of heptane and the resultingsolution was heated to 40° C.±10° C. for 15 minutes. The heat wasremoved and the solution was seeded and stirred overnight. The productcrystallized on the walls of the reactor and was resuspended in 80 kg oftoluene, reconcentrated at not more than 50° C. to approximately 130 L,then 45.2 kg of heptane was added. The resulting solution was thenheated to 40° C.±10° C. for not less than 15 minutes and then cooled atnot more than 20° C./hour to 18° C.±5° C. After not less than 12 hours,the resulting white slurry was cooled to 14° C.±5° C. and stirred fornot less than 3 hours. The white slurry was filtered and the solidwashed with 41 kg of 1:1 toluene/heptane. The solid product was dried atnot more than 50° C. to provide the desired product (47.8 kg) as a whitepowder.

B. 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

A mixture of N-phenoxycarbonyl-L-valine (25 g, 0.106 mol) and3-chloropropylamine hydrochloride (15.2 g, 0.116 mol) in THF (250 mL)was cooled to 2° C. Sodium hydroxide (12.7 g, 0.318 mol) was added tothe stirring suspension. After about 35 minutes, a slow exotherm to 10°C. occurred. The reaction was stirred at less than 10° C. for 2 hours. Asolution of potassium t-butoxide (29.6 g, 0.265 mol) in 125 mL of THFwas added over 10 minutes, followed by a 20 mL THF rinse. Thetemperature of the reaction mixture was allowed to rise to 20° C. duringthe addition. The reaction mixture was stirred at room temperature for19 hours.

The reaction mixture was quenched with 200 mL of distilled water andthen acidified to pH 9 using 26.2 g of concentrated hydrochloric acid,keeping the temperature below 30° C. The aqueous layer was separated andwashed with another 125 mL of THF. Ethanol 3A (75 mL) was added to theseparated aqueous layer and the mixture was acidified to pH<3 with 12.3g of concentrated hydrochloric acid, keeping the temperature below 25°C. The acidified mixture was extracted twice with ethyl acetate (250 mLand 150 mL). The combined organic layers were evaporated to dryness on arotary evaporator at a temperature below 50° C. The residual solids wereflushed with 250 mL of ethyl acetate. The residual solid was dissolvedin 150 mL of ethanol 3A at reflux temperature and filtered through a 5 gDarco-G60 bed over filteraid, followed by a 50 mL hot ethanol rinse. Thefiltrate was evaporated to dryness on a rotary evaporator at atemperature below 50° C. Ethyl acetate (75 mL) was added to the residueand refluxed for 30 minutes. The suspension was cooled to below 10° C.for 2 hours. The solid was collected by filtration and washed with 20 mLof cold ethyl acetate (5-8° C.). After drying at 40° C. for 72 hours thedesired product was obtained as a white solid (15.6 g, 74%).

EXAMPLE 36 Alternative Preparation of2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

A mixture of phenoxycarbonyl-L-valine (250 g, 1.05 mol; preparedaccording to the procedure disclosed in U.S. patent application Ser. No.08/671,893, filed Jun. 28, 1996, which is incorporated herein byreference) and 3-chloropropylamine hydrochloride (151 g, 1.16 mol) inTHF (2.5 L) is cooled to 2° C. Sodium hydroxide (127 g, 3.2 mol) isadded to the stirring suspension. After about 45 minutes, a rapidexotherm to 10° C. occurrs. The reaction is stirred at 1-5° C. for 2hours. Additional 3-chloropropylamine (10 g, 0.08 mol) is added andstirring is continued for 1 hour. A solution of potassium t-butoxide(296 g, 2.6 mol) in 1.25 L of THF is then added over 30 minutes,followed by a 100 mL THF rinse. The temperature of the reaction mixturewas allowed to rise to 20° C. during the addition. The reaction mixtureis stirred at room temperature for 12-16 hours.

The reaction mixture is quenched with 2 L of distilled water and cooledto 12° C. and then acidified to pH 9 using 258 g (2.6 mol) ofconcentrated hydrochloric acid, keeping the temperature below 30° C. Theaqueous layer is separated. Ethanol 3A (625 mL) is added to theseparated aqueous layer and the mixture was acidified to pH<3 with 116 g(1.2 mol) of concentrated hydrochloric acid, keeping the temperaturebelow 25° C. The acidified mixture is extracted twice with ethyl acetate(2.5 L and 1.5 L). The combined organic layers are evaproated to drynesson a rotary evaporator at a temperature below 50° C. The residual solidsare dried by repeated distillation with ethyl acetate (4×1 L). Theresidual solid is dissolved in 750 mL of methanol and treated withdecolorizing carbon (10 g Darco-G60 bed) at room temperature overnight.The carbon is removed by filtration through diatomaceous earth. Thefiltrate is evaporated to dryness on a rotary evaporator at atemperature below 50° C. Ethyl acetate (1.5 L) is added to the residueand approximately 500 mL is removed on the rotary evaporator. Thesuspension is cooled to below 10° C. for >1 hour. The solid is collectedby filtration and washed with 2×100 mL of cold ethyl acetate (5-8° C.).After drying at 50° C. for 72 hours the desired product is obtained.

EXAMPLE 37 Alternative Preparation of2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

A. (S)-(-)-N-carboxymethyl-N(β)cyanoethyl Valine

To a 5 L 3-neck round bottom flask with a mechanical stirrer was added(S)-valine (170.1 g, 1.45 mol) and water 145 mL. The solution was cooledto 20° C. with an ice-water bath and a solution of 1.0 eq of KOH (93 gof 88% solid KOH) in 180 mL water was added dropwise over 20 minutes.After the addition was complete, acrylonitrile 1.0 eq (95.5 mL) wasadded dropwise with vigorous stirring while maintaining the internaltemperature of the flask below 5° C. The solution was allowed to stirbetween 0-5° C. for 4.5 h. Water (600 mL) was added and a pH meter wasinserted into the solution. Methyl chloroformate 1.0 eq (112 mL) wasadded dropwise while maintaining the pH of the solution between 9.5 and10.5, with solution of 10% aq KOH. The addition took place over 0.5 h.The solution was then acidified with conc. HCl and phosphoric acid to pH2 and was subsequently extracted with 2 L of isopropyl acetate. Theorganic layer was concentrated under vacuum to give 201 g (60%) of acolorless oil that solidified on standing. mp 65-66° C. Optical rotationsodium D line at 25° C.-0.44 (c=4.3, ethanol). IR (cm⁻¹, CDCl₃) 2960,1740, 1710, 1470. ¹ H NMR (300 MHz, CDCl₃); (δ TMS, 0.00) ppm 0.93 (d,3H J=7 Hz); 1.07 (d,3H J=6 Hz); 2.16-2.36 (m, 1H); 2.62-2.86 (m, 2H);3.62 (t, 2H, J=7.5 Hz); 3.77 (s, 1.2H rotamer); 3.82 (s, 1.8H rotamer);4.15-4.30 (m, 1H); 9.76-9.96 (brs, 1H). ms (DCl/NH₃) 246, 185, 146, 125.FAB hrms: cal for (M+H⁺): 229.1188; found: 229.1185.

B. 2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid

To a 2 L pressure vial was added the product of Example 37A (190 g,0.833 mol), water (900 mL) and KOH (3 eq, 140 g). To this solution atambient temperature was added Nickel Aluminum alloy (Raney-Type) 75 g.Note that this is the unactivated form. The solution was sealed in apressure bomb and was placed under 60 psi of hydrogen. The resultingsolution was heated to 100° C. for 4 h. After cooling the solution toambient temperature, it was filtered, washed with 900 mL ofdichloromethane and subsequently acidified to pH 1. The aqueous solutionwas extracted with 2×900 mL of dichloromethane. The combined organiclayers were concentrated to give 120 g of crude product which wasslurried in isopropyl acetate to give 70 g of the title compound.

EXAMPLE 38 Alternative Preparation of(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A-1,2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride

2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (17.6 g, 87.9mmole) was slurried in THF (240 mL) and cooled to <5° C. Thionylchloride (14.3 g, 120 mmole) was added over 5 minutes (exothermic). Theslurry was stirred at 20° C. for 70 min. until complete by HPLC (samplesquenched into methanol). THF was removed by rotary evaporation; heptane(90 mL) was added and removed by rotary evaporation, yielding a wetsolid mass. The material was slurried in DMF (85 mL).

A-2. Alternative Preparation of2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride

2S-(1-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (39.6 g, 198mmole) was slurried in THF (590 mL) and cooled to 1° C. Thionyl chloride(28.3 g, 238 mmole) was added over 5 minutes (exothermic). The slurrywas stirred at 20° C. for 2 hours. THF was removed on the rotaryevaporator; THF (200 mL) was added and removed on the rotary evaporator,yielding a wet solid mass. The material was slurried in DMF (225 mL).

B-1. (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

(2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane (ca.83 mmole, U.S. Pat. No. 5,491,253, issued Feb. 13, 1996, which isincorporated herein by reference) and imidazole (8.2 g, 120 mmole) weredissolved in ethyl acetate (350 mL, KF<0.1%) and cooled to 2° C. Theslurried product of Example 38A-1 was added (exothermic, maximum temp.was 10° C.), followed by a DMF rinse (15 mL). The reaction was stirredcold initially then allowed to slowly warm to room temperature andstirred overnight.

The reaction was quenched with 100 mL water and stirred 30 minutes. Theorganic layer was separated and washed with 3×125 mL 5% NaCl. Theorganic solution was filtered and concentrated on rotary evaporator to athick syrup, 62 g. HPLC purity approx. 85% (peak area). Isomer contentapprox. 11.2%.

CIMS (NH₃) m/z 647 (M+H)⁺.

¹ H NMR (300 MHz, CDCl₃) δ7.35-7.13 (m, 10H), 7.13-7.06 (m, 1H), 6.87(br d, 1H), 5.22 (br s, 1H), 4.28 (d, 1H), 4.20-4.05 (m, 1H), 3.95 (d,2H), 3.65-3.56 (m, 1H), 3.37, (d, 2H), 3.12-2.89 (m, 5H), 2.83-2.53 (m,4H), 2.23-2.08 (m, 1H), 1.74-1.40 (m, 4H), 0.87-0.75 (m, 6H).

¹³ C NMR (75 MHz, CDCl₃) δ170.0, 156.6, 140.2, 139.1, 138.4, 129.3,129.1, 128.9, 128.4, 128.3, 128.0, 127.1, 126.0, 125.8, 69.1, 64.0, 63.1(br), 54.2, 49.2, 41.2, 40.5, 40.0, 39.7, 31.5, 25.4, 21.6, 19.5, 18.6.

B-2. Alternative Preparation of(2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

(2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane (ca.180 mmole; U.S. Pat. No. 5,491,253, issued Feb. 13, 1996, which isincorporated herein by reference) and imidazole (38.1 g, 560 mmole) weredissolved in ethyl acetate (675 mL, KF<0.1%) and cooled to 1° C. Theslurried product of Example 38A-2 was added slowly over 30 minutes(exothermic, maximum temp. was 6° C.), followed by an ethyl acetaterinse (225 mL). The reaction was stirred cold for 1.5 hours, thenallowed to slowly warm to about 27° C. and stirred for about 20 hours.

The reaction was quenched with a dilute solution of HCl (36.75 gconcentrated HCl in 225 mL of water) and stirred 20 minutes. Thebiphasic mixture was filtered with a 100 mL ethyl acetate rinse. Theorganic layer was separated and washed with 3×125 mL 5% NaCl. Theorganic layer was separated and washed with 3×225 mL 5% NaCl and 2×225mL 5% NaHCO₃. The organic solution was concentrated by rotaryevaporation to provide the desired product as a thick syrup.

C. (2S,3S,5S)-2-Amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

The crude product of Example 38B (ca. 83 mmole) was dissolved inmethanol (260 mL). Pd/C (50% wet Pearleman's catalyst, 10.4 g wetweight) and ammonium formate (15.1 g, 239 mmole) were added and themixture was warmed to 50° C. After 2.5 hours the reaction was completeby TLC. The mixture was cooled to 35° C. and catalyst was removed byfiltration through diatomaceous earth, followed by a methanol rinse (250mL). The combined filtrate was concentrated on the rotary evaporator.The residue was dissolved in dioxane (150 mL) with warming. Dioxane wasremoved on the rotary evaporator to yield 60 g of yellow oil. HPLCpurity approx. 88.2% (peak area). Isomer content ≧7.9% (however, oneisomer does not separate from the main peak).

CIMS (NH₃) m/z 467 (M+H)⁺

¹ H NMR (300 MHz, CD₃ OD) δ7.35-7.10 (m, 1OH), 4.40-4.20 (m, 1H), 4.25(d, 1H), 3.68-3.57 (m, 1H), 3.20-3.09 (m, 2H), 3.08-2.90 (m, 3H),2.90-2.74 (m, 2H), 2.65-2.49 (m, 2H), 2.20-2.04 (m, 1H), 1.92-1.78 (m,1H), 1.78-1.60 (m, 2H), 1.60-1.45 (m, 1H), 0.88-0.77 (m, 6H)

¹³ C NMR (75 MHz, CD₃ OD) δ171.3, 158.4, 140.5, 139.8, 130.6, 130.4,129.5, 129.3, 127.3, 127.0, 71.5, 63.9, 57.1, 49.1, 41.8, 41.6, 41.4,40.7, 40.5, 26.9, 22.5, 20.0, 18.9

¹ H NMR (300 MHz, CDCl₃) δ7.35-7.13 (m, 10H), 5.35 (s, 1H), 4.40-4.23(m, 2H), 3.60-3.52 (m, 1H), 3.25-2.65 (m, 8H), 2.58-2.45 (dd, 1H),2.30-2.10 (m, 1H), 1.90-1.65 (m, 3H), 1.65-1.50 (m, 1H), 0.91 (d, 3H),0.84 (d, 3H)

¹³ C NMR (75 MHz, CDCl₃) δ171.2, 156.6, 139.1, 138.5, 129.3, 129.2,128.5, 128.2, 126.3, 126.0, 71.6, 63.1 (br), 56.3, 48.7, 41.6, 41.0,40.6, 40.0, 39.6, 25.5, 21.7, 19.7, 18.7

D. (2S,3S,5S)-2-Amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane(S)-Pyroglutamic acid salt

The crude product of Example 38C was dissolved in dioxane (370 mL,KF=0.07% moisture). S-Pyroglutamic acid (10.3 g, 80 mmole) was added andthe suspension was warmed to 50° C. to give a clear solution. Afterstirring 1 hour the solution was seeded with a few crystals of theproduct salt. The salt slowly precipitated. The slurry was slowly cooledand stirred overnight at room temperature. The product was isolated byfiltration and washed with dioxane (100 mL). Wet cake weight was 120 g.Product was dried at 60° C. in a vacuum oven with nitrogen purge. Yield35.2 g off-white powder. HPLC purity: >98% (peak area includingpyroglutamic acid). Isomer content approx. 1% (however, one isomer doesnot separate from the main peak).

mp=135-141° C.

a!_(D) ²⁵ =-21.9° (c=2.5, CH₃ OH)

CIMS (NH₃) m/z 467 (M+H for base)⁺, 147 (M+NH₄ for pyroglutamic acid)⁺,130 (M+H for pyroglutamic acid)⁺

IR (KBr) 1586, 1655, 1682 cm⁻¹

¹ H NMR (400 MHz, DMSO-d₆) δ7.62 (s, 1H), 7.54 (d, 1H), 7.32-7.06 (m,10H), 6.33 (s, 1H), 4.26 (d, 1H), 4.11-3.99 (m, 1H), 3.82 (dd, 1H),3.57-3.48 (m, 1H), 3.27-3.19 (m, 1H), 3.08-2.95 (m, 2H), 2.92-2.70 (m,5H), 2.53-2.43 (m, 1H), 2.26-2.14 (m, 1H), 2.13-1.99 (m, 2H), 1.99-1.87(m, 2H), 1.72-1.61 (m, 2H), 1.61-1.49 (m, 1H), 1.46-1.35 (m, 1H), 0.70(d, 3H), 0.64 (d, 3H).

¹³ C NMR (100 MHz, DMSO-d₆) δ176.9, 176.1, 169.2, 155.5, 138.8, 137.7,129.3, 129.3, 128.3, 127.8, 126.4, 125.5, 66.9, 61.5, 56.9, 55.3, 46.8,40.2, 39.6, 39.4, 38.8, 37.4, 29.8, 25.4, 25.3, 21.6, 19.6, 18.7.

¹ H NMR (300 MHz, CD₃ OD) δ7.32-7.03 (m, 10H), 4.23-4.12 (m,1H), 4.12(d, 1H), 3.98 (dd, 1H), 3.71-3.63 (m, 1H), 3.46-3.37 (m, 1H), 3.11-2.98(m, 2H), 2.97-2.80 (m, 4H), 2.70-2.59 (m, 1H), 2.49-2.38 (m, 1H),2.38-2.12 (m, 3H), 2.07-1.92 (m, 2H), 1.75-1.63 (m, 2H), 1.63-1.50 (m,1H), 1.45-1.32 (m, 1H), 0.74-0.65 (m, 6H).

¹³ C NMR (75 MHz, CD₃ OD) δ181.0, 179.6, 171.6, 158.4, 139.5, 137.3,130.5, 130.0, 129.4, 128.3, 127.2, 68.1, 64.0, 59.6, 57.7, 48.8, 41.7,41.1, 40.7, 40.6, 37.9, 31.1, 26.9, 26.9, 22.5, 20.1, 18.9.

¹ H NMR (300 MHz, D₂ O) δ7.30-6.97 (m, 10H), 4.16-4.03 (m, 1H),3.99-3.91 (m, 2H), 3.71-3.63 (m, 1H), 3.43-3.35 (m, 1H), 3.00-2.68 (m,6H), 2.40-2.13 (m, 5H), 1.88-1.72 (m, 3H), 1.68-1.56 (m, 1H), 1.52-1.37(m, 1H), 1.32-1.18 (m, 1H), 0.60-0.52 (m, 6H).

¹³ C NMR (75 MHz, D₂ O) δ181.6, 180.1, 171.0, 157.3, 137.9, 135.2,129.3, 129.2, 129.1, 128.4, 127.6, 126.4, 67.3, 62.6, 58.2, 56.7, 47.5,40.1, 39.4, 39.2, 38.7, 35.7, 29.6, 25.3, 25.2, 20.5, 18.5, 17.6.

E. (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

The product of Example 1H (7.26 g, 40.3 mmole) was slurried in ethylacetate (22 mL) and thionyl chloride (5.75 g, 48.3 mmole) was added,followed by 1 drop DMF. The mixture was warmed to 50° C. and stirred 5hours. The solution of the resulting acid chloride was cooled to 22° C.and held for the subsequent coupling reaction.

The product of Example 38D (20 g, 31.7 mmole, corrected for dioxanecontent), sodium bicarbonate (16.5 g, 197 mmole), ethyl acetate (150 mL)and water (150 mL) were combined in a flask and stirred until theproduct of Example 38D had dissolved (some salt remains undissolved).The solution of acid chloride prepared above was added over 5 minutes,followed by an ethyl acetate rinse (5 mL). Addition was mildlyexothermic (maximum temperature 23° C.). The mixture was stirredovernight.

The organic layer was separated and washed with 5% sodium bicarbonate(100 mL) and water (100 mL). Solvent was removed on the rotaryevaporator. The residue was dissolved in ethyl acetate (100 mL) andfiltered, rinsing with ethyl acetate (50 mL). The solvent was removedfrom the combined filtrate on the rotary evaporator. The residue wasdissolved in hot ethyl acetate (105 mL) and heptane (105 mL) was added;product began to crystallize rapidly. The slurry was cooled and stirredat 20-23° C. for 5 hours. Product was collected by filtration and washedwith 1/1 (v/v) ethyl acetate/heptane (30 mL). Product was dried undervacuum oven at 70° C. to provide 18.8 g of the desired product as awhite powder.

EXAMPLE 39 Preparation of Amorphous(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A. The product of Example 38E (2.5 g) was dissolved in 8 mL of absoluteethanol. This solution was added slowly dropwise to 250 mL of chilledwater at 9° C. with vigorous stirring. A white solid immediatelyappeared. The stirring was continued for 15 minutes and the solids werecollected by filtration. Vacuum drying at 50° C. for 12 hours provided2.32 g of the desired product as an amorphous solid.

B. The product of Example 38E (2.5 g) was dissolved in 6 mL of absoluteethanol. This solution was added slowly dropwise to 31 mL of chilledwater at 7-9° C. with vigorous stirring. A white solid appeared. Thestirring was continued for 20 minutes and the solids were collected byfiltration. Vacuum drying at 50° C. for 12 hours provided 2.24 g of thedesired product as an amorphous solid.

C. The product of Example 38E (0.5 g) was dissolved in 8 mL ofisopropanol. This solution was added slowly dropwise to 100 mL ofchilled water at 10-15° C. with vigorous stirring. A white solidappeared. The stirring was continued for 20 minutes and the solids werecollected by filtration. Air drying provided 0.48 g of the desiredproduct as an amorphous solid.

D. The product of Example 38E (0.5 g) was dissolved in 8 mL of acetoneand 0.2 mL of absolute ethanol. This solution was added slowly dropwiseto 100 mL of chilled water at 10-15° C. with vigorous stirring. A whitesolid appeared. The stirring was continued for 10 minutes and the solidswere collected by filtration. Air drying provided 0.46 g of the desiredproduct as an amorphous solid.

E. The product of Example 38E (0.5 g) was dissolved in 2 mL ofacetonitrile. This solution was added slowly dropwise to 100 mL ofchilled water at 10-15° C. with vigorous stirring. A white solidappeared. The stirring was continued for 20 minutes and the solids werecollected by filtration. Air drying provided 0.46 g of the desiredproduct as an amorphous solid.

EXAMPLE 40 N-(3-Chloropropylaminocarbonyl)-valine methyl ester

3-Chloropropylisocyanate (0.31 mL, 3.0 mmol) was added to a slurry ofL-valine methyl ester hydrochloride (0.5 g, 3.0 mmol) and triethylamine(0.42 mL, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred for4 hours at room temperature and was then quenched with the addition ofaqueous sodium bicarbonate. The quenched reaction mixture was extractedwith ethyl acetate. The organic layer was separated, dried andevaporated to give the desired product.

EXAMPLE 41 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-4-hydroxy-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

Reaction of a solution of the product of Example 25E in methylenechloride with sodium borohydride provides the desired product.

EXAMPLE 42 (2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-6-hydroxy-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane

A 300-mL incubation of(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-6-hydroxy-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane labelled with ¹⁴ C in the carbonylgroup of the acetyl moiety (50 μM, 6.0 μCi) was performed with rat livermicrosomes (0.5 mg/mL microsomal protein) and an NADPH-generating systemfor 60 minutes at 37° C. The metabolic reaction was stopped by adding300 mL of acetonitrile. The supernatant obtained after centrifugation at3000 RPM for 10 minutes was evaporated to dryness in vacuo. The residuewas reconstituted in 2 mL of HPLC mobile phase. Isolation of the desiredproduct was achieved at ambient temperature with a Beckman Ultrasphere 5μm 10×150 mm C₁₈ column connected to an Alltech Ultrasphere 5 μm C₁₈cartridge guard column. A linear gradient of 25-55% acetonitrile inbuffer (25 mM ammonium acetate, pH adjusted to 4.8 with formic acid)over 57 minutes was used as column eluent at a flow rate of 2.8mL/minute.

Fluorogenic Assay for Screening Inhibitors of HIV Protease

The inhibitory potency of the compound of the invention can bedetermined by the following method.

The compound of the invention is dissolved in DMSO and a small aliquotfurther diluted with DMSO to 100 times the final concentration desiredfor testing. The reaction is carried out in a 6×50 mm tube in a totalvolume of 300 microliters. The final concentrations of the components inthe reaction buffer are: 125 mM sodium acetate, 1M sodium chloride, 5 mMdithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 μM fluorogenicsubstrate, 2% (v/v) dimethylsulfoxide, pH 4.5. After addition ofinhibitor, the reaction mixture is placed in the fluorometer cell holderand incubated at 30° C. for several minutes. The reaction is initiatedby the addition of a small aliquot of cold HIV protease. Thefluorescence intensity (excitation 340 nM, emmision 490 nM) is recordedas a function of time. The reaction rate is determined for the first sixto eight minutes. The observed rate is directly proportional to themoles of substrate cleaved per unit time. The percent inhibition is100×(1-(rate in presence of inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Gaba-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANSwherein DABCYL=4-(4-dimethylamino-phenyl)azobenzoic acid,Gaba=γ-aminobutyric acid, andEDANS=5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid.

                  TABLE 1    ______________________________________    Compound of  Percent  Inhibitor Concentration    Example      Inhibition                          (nanomolar)    ______________________________________     1P          92.6     0.5     2B          93.2     0.5     3C          86.9     0.5     4F          49.7     0.5     5           80.8     0.5     6F          61.4     0.5     7B          67.1     0.5     8           55.6     0.5     9B          62.6     0.5    10F          81.0     0.5    11B          91.1     0.5    12B          76.8     0.5    13B          56.2     1.0    14D          52.7     0.5    15           48       0.5    17C          87.2     0.5    18C          57.8     0.5    19E          68.5     0.5    22E          71.8     0.5    23C          86.0     0.5    25E          100      0.5    26H          94.6     0.5    27D          92.9     0.5    28           86.6     0.5    29C          72.6     0.5    36B          91.0     0.5    ______________________________________

Antiviral Activity

The anti-HIV activity of the compound of the invention can be determinedin MT4 cells according to the following procedure. MT4 cells wereinfected with cell-free supernatant of HIVIIIB (previously frozen withknown 50% tissue culture infectious dose (TCID₅₀) at 0.003 multiplicityof infection (MOI) for one hour. After one hour infection, cells werewashed twice to remove residual viruses, resuspended in culture mediaand seeded into 96-well tissue culture plates at 1×10 4 cells per wellwith various half-log dilutions of compounds. Uninfected cells areincluded as toxicity and cell controls. RPMI 1640 media (Gibco) with 10%fetal bovine serum were used as culture media. Various concentrations ofhuman serum (Sigma) 50%, 25% and 12.5% were added to culture mediaresulting in final concentration of 60%, 35% and 22.5% total serum. Allassay plates were incubated in 37 deg. cent. incubator for 5 days. MTT(sigma, 5 mg/ml stock in PBS) was added to all wells at 25 ul per well,incubate for 4 hours. 20% SDS with 0.02N HCl in water was added at 50 ulper well to lyse cells. Plates incubated overnight for complete lyseswere read on a microtitre plate reader at 570/650 nm wavelengths todetermine cell optical density (O.D.). Raw data were analysed forpercent inhibition by the following formula: ##EQU1## The 50% effectiveconcentration (EC₅₀) was calculated by the median effect equation (Chou,1975, Proc. Int. Cong. Pharmacol. 6th p. 619) to determine the efficacyof compound. The 50% lethal concentration (LC₅₀) was calculated usinguninfected MT4 cells.

Under these conditions, the following data were obtained (n=4 duplicatedeterminations:

                  TABLE 2    ______________________________________    Compound of    IC.sub.50   LC.sub.50    Example        (μM, 0% plasma)                               (μM)    ______________________________________     1P            0.01        41.32     2B            0.016       17.78     3C            0.025       49.5     4F            0.101       >100     5             0.368       >100     6F            0.193       >100     7B            0.204       >100     8             0.019       17.78     9B            0.272       19.33    10F            0.047       91.97    11B            0.19        18.16    12B            0.093       19.11    14D            0.053       >100    15             0.119       >100    17C            0.051       18.96    18C            0.329       19.1    19E            0.395       17.95    20D            0.283       24.08    25E            0.012       22.88    26H            0.015       33.0    27D            0.03        56.23    28             0.011       72.2    29C            0.427       56    30B            0.003       18    ______________________________________

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases.

Preferred salts of the compounds of the invention include hydrochloride,methanesulfonate, sulfonate, phosphonate and isethionate.

The compounds of the present invention can also be used in the form ofesters. Examples of such esters include compounds wherein a hydroxylgroup in the compound of this invention has been acylated with anN-protected or unprotected amino acid residue, a phosphate function, ahemisuccinate residue, an acyl residue of the formula R*C(O)-- orR*C(S)-- wherein R* is hydrogen, loweralkyl, haloalkyl, alkoxy,thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acylresidue of the formula R_(a) --C(R_(b))(R_(d))--C(O)-- or R_(a)--C(R_(b))(R_(d))--C(S)-- wherein R_(b) and R_(d) are independentlyselected from hydrogen or loweralkyl and R_(a) is --N(R_(e))(R_(f)),OR_(e) or --SR_(e) wherein R_(e) and R_(f) are independently selectedfrom hydrogen, loweralkyl and haloalkyl, or an amino-acyl residue of theformula R180NH(CH₂)₂ NHCH₂ C(O)-- or R₁₈₀ NH(CH₂)₂ OCH₂ C(O)-- whereinR₁₈₀ is hydrogen, loweralkyl, arylalkyl, cycloalkylalkyl, alkanoyl,benzoyl or an α-amino acyl group. The amino acid esters of particularinterest are glycine and lysine; however, other amino acid residues canalso be used, including those wherein the amino acyl group is --C(O)CH₂NR₂₀₀ R₂₀₁ wherein R₂₀₀ and R₂₀₁ are independently selected fromhydrogen and loweralkyl or the group --NR₂₀₀ R₂₀₁ forms a nitrogencontaining heterocyclic ring. These esters serve as pro-drugs of thecompound of the present invention and serve to increase the solubilityof these substances in the gastrointestinal tract. These esters alsoserve to increase solubility for intravenous administration of thecompound. Other prodrugs include compounds wherein a hydroxyl group inthe compound of this invention is functionalized with a substituent ofthe formula --CH(R_(g))OC(O)R₁₈₁ or --CH(R_(g))OC(S)R₁₈₁ wherein R₁₈₁ isloweralkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R_(g) ishydrogen, loweralkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can beprepared according to the procedure of Schreiber (Tetrahedron Lett.1983, 24, 2363) by ozonolysis of the corresponding methallyl ether inmethanol followed by treatment with acetic anhydride.

The prodrugs of this invention are metabolized in vivo to provide thecompound of this invention. The preparation of the prodrug esters iscarried out by reacting the compound of the invention with an activatedamino acyl, phosphoryl, hemisuccinyl or acyl derivative as definedabove. The resulting product is then deprotected to provide the desiredpro-drug ester. Prodrugs of the invention can also be prepared byalkylation of the hydroxyl group with (haloalkyl)esters,transacetalization with bis-(alkanoyl)acetals or condensation of thehydroxyl group with an activated aldehyde followed by acylation of theintermediate hemiacetal.

The compounds of the invention are useful for inhibiting retroviralprotease, in particular HIV protease, in vitro or in vivo (especially inmammals and in particular in humans). The compounds of the presentinvention are also useful for the inhibition of retroviruses in vivo,especially human immunodeficiency virus (HIV). The compounds of thepresent invention are also useful for the treatment or prophylaxis ofdiseases caused by retroviruses, especially acquired immune deficiencysyndrome or an HIV infection in a human or other mammal.

Total daily dose administered to a human or other mammal host in singleor divided doses may be in amounts, for example, from 0.001 to 300 mg/kgbody weight daily and more usually 0.1 to 20 mg/kg body weight daily.Dosage unit compositions may contain such amounts of submultiplesthereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The compounds of the present invention may be administered orally,parenterally, sublingually, by inhalation spray, rectally, or topicallyin dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologically aceptableand metabolizable lipid capabale of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to thecompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natureal and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Some preferred dosage forms for the compounds of this invention aredisclosed in U.S. patent application Ser. No. 08/754,390, filed Nov. 21,1996, now abandoned, in the names of J. Lipari, L. A. Al-Razzak, S.Ghosh and R. Gao and which is entitled Pharmaceutical Composition, whichis incorporated herein by reference.

A preferred dosage form for the compounds of this invention comprises asolution of (a) a compound of the formula I in the amount of from about1% to about 50% (preferably, from about 5% to about 30%) by weight ofthe total solution and (b) polyoxyl 35 castor oil in the amount of fromabout 0% to about 20% (preferably, from about 5% to about 10%) by weightof the total solution, in a pharmaceutically acceptable organic solventwhich comprises (i) oleic acid in the amount of from about 20% to about99% (preferably, from about 30% to about 70%; more preferably, fromabout 40% to about 65%) by weight of the total solution or (ii) amixture of (1) oleic acid in the amount of from about 20% to about 99%(preferably, from about 30% to about 70%; more preferably, from about40% to about 65%) by weight of the total solution and (2) ethanol orpropylene glycol or a mixture thereof in the amount of from about 0% toabout 12% (preferably, about 10%) by weight of the total solution. In aneven more preferred embodiment of the invention, the solution isencapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatincapsule.

A most preferred composition of the invention comprises a solution of(a) a compound of the formula I in the amount of about 30% by weight ofthe total solution and (b) polyoxyl 35 castor oil in the amount of about10% by weight of the total solution, in a pharmaceutically acceptableorganic solvent which comprises a mixture of (1) oleic acid in theamount of about 50% by weight of the total solution and (2) ethanol inthe amount of about 10% by weight of the total solution. In a mostpreferred embodiment of the invention, the solution is encapsulated in asoft elastic gelatin capsule (SEC) or a hard gelatin capsule and thesolution also comprises an antioxidant (preferably, BHT (butylatedhydroxytoluene)) in the amount of from about 0.01% to about 0.08% byweight of the total solution (preferably, from about 0.01% to about0.05% by weight of the total solution).

An example of such a composition and its preparation is provided below.

    ______________________________________    Component             % By Weight    ______________________________________    compound of Example 2B (free base)                          30    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          10    Oleic acid, 6321, NF  50    Butylated hydroxy toluene (BHT), NF                          0.01    ______________________________________

Preparation of the above composition

The mixing tank was purged with nitrogen. Oleic acid (499.9 g) andethanol (100 g) were mixed in the tank. The butylated hydroxytoluene(0.1 g) was charged into the tank and mixed until the solution wasclear. The Compound of Example 2B (300 g) was slowly charged into thetank and mixed until the solution was clear. The polyoxyl 35 castor oil(100 g) was added to the tank and mixed. The resulting solution wasfilled into soft elastic capsules (0.333 g of solution/SEC) to provide adosage of 100 mg of compound of Example 2B/SEC or 0.667 g/SEC to providea dosage of 200 mg of compound of Example 2B/SEC.

While the compound of the invention can be administered as the soleactive pharmaceutical agent, it can also be used in combination with oneor more immunomodulators, antiviral agents, other antiinfective agentsor vaccines. Other antiviral agents to be administered in combinationwith a compound of the present invention include AL-721, betainterferon, polymannoacetate, reverse transcriptase inhibitors (forexample, dideoxycytidine (ddC; zalcitabine), dideoxyinosine (ddI;didanosine), BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC(lamivudine) DP-AZT, FLT (fluorothymidine), BCH-189,5-halo-3'-thia-dideoxycytidine, PMEA, bis-POMPMEA, zidovudine (AZT),nevirapine, delviridine, MSA-300, trovirdine and the like),non-nucleoside reverse transcriptase inhibitors (for example, R82193,L-697,661, BI-RG-587 (nevirapine), retroviral protease inhibitors (forexample, HIV protease inhibitors such as ritonavir, Ro 31-8959(saquinavir), SC-52151, VX-478, AG1343 (nelfinavir), BMS 186,318,SC-55389a, BILA 1096 BS, DMP-323, DMP-450, KNI-227, KNI-272, U-140690,N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide(MK-639; indinavir),5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide,1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide(i.e., 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu),5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide(i.e., iQoa-Mta-Apns-Thz-NHtBu) and the like), HEPT compounds,L,697,639, R82150, U-87201E and the like), HIV integrase inhibitors(Zintevir and the like), TAT inhibitors (for example, RO-24-7429 and thelike), trisodium phosphonoformate, HPA-23, eflonithine, Peptide T,Reticulose (nucleophosphoprotein), ansamycin LM 427, trimetrexate,UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G,cyclobut-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, L-693,989,BV ara-U, CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109,TI-23, trifluridine, vidarabine, famciclovir, penciclovir, acyclovir,ganciclor, castanosperminem rCD4/CD4-IgG, CD4-PE40, butyl-DNJ,hypericin, oxamyristic acid, dextran sulfate and pentosan polysulfate.Immunomodulators that can be administered in combination with thecompound of the present invention include bropirimine, Ampligen,anti-human alpha interferon antibody, colony stimulting factor,CL246,738, Imreg-1, Imreg-2, diethydithiocarbamate, interleukin-2,alpha-interferon, inosine pranobex, methionine enkephalin,muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosisfactor, beta interferon, gamma interferon, interleukin-3, interleukin-4,autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1,anti-Leu-3A, autovaccination, biostimulation, extracorporealphotophoresis, cyclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CSF,hyperthermia, isopinosine, IVIG, HIVIG, passive immunotherapy and poliovaccine hyperimmunization. Other antiinfective agents that can beadministered in combination with the compound of the present inventioninclude pentamidine isethionate. Any of a variety of HIV or AIDSvaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1e(gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160),HGP-30, HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be usedin combination with the compound of the present invention.

Other agents that can be used in combination with the compound of thisinvention are ansamycin LM 427, apurinic acid, ABPP, Al-721, carrisyn,AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetylcysteine, (2-oxothiazolidine-4-carboxylate), D-penicillamine,diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23,human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or otherquinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin,MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng,pentofylline, pentoxifylline, Peptide T, pine cone extract,polymannoacetate, reticulose, retrogen, ribavirin, ribozymes, RS-47,Sdc-28, silicotungstate, THA, thymic humoral factor, thymopentin,thymosin fraction 5, thymosin alpha one, thymostimulin, UA001, uridine,vitamin B12 and wobemugos.

Other agents that can be used in combination with the compound of thisinvention are antifungals such as amphotericin B, clotrimazole,flucytosine, fluconazole, itraconazole, ketoconazole and nystatin andthe like.

Other agents that can be used in combination with the compound of thisinvention are antibacterials such as amikacin sulfate, azithromycin,ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol,isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65and the like.

Other agents that can be used in combination with the compound of thisinvention are anti-neoplastics such as alpha interferon, COMP(cyclophosphamide, vincristine, methotrexate and prednisone), etoposide,mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide,vincristine and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate(w/leucovin rescue), doxorubicin, cyclophosphamide, taxol,etoposide/mechlorethamine, vincristine, prednisone and procarbazine),vincristine, vinblastine, angioinhibins, pentosan polysulfate, plateletfactor 4 and SP-PG and the like.

Other agents that can be used in combination with the compound of thisinvention are drugs for treating neurological disease such as peptide T,ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparinand cytosine arabinoside and the like.

Other agents that can be used in combination with the compound of thisinvention are anti-protozoals such as albendazole, azithromycin,clarithromycin, clindamycin, corticosteroids, dapsone, DIMP,eflornithine, 566C80, fansidar, furazolidone, L,671,329, letrazuril,metronidazole, paromycin, pefloxacin, pentamidine, piritrexim,primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine,trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.

Among the preferred agents for inhibition or treatment of HIV or AIDS incombination with the compound of this invention are reversetranscriptase inhibitors, especially, AZT (zidovudine), ddI(didanosine), ddC (zalcitabine), d4T (stavudine), 3TC (lamivudine),nevirapine, delviridine, trovirdine, PMEA, bis-POMPMEA and MSA-300.

Other preferred agents for inhibition or treatment of HIV or AIDS incombination with the compound of this invention are HIV proteaseinhibitors, especially, ABT-538 (ritonavir) and related compounds,disclosed in U.S. Pat. No. 5,541,206, issued Jul. 30, 1996 and U.S. Pat.No. 5,491,253, issued Feb. 13, 1996 which are both incorporated byreference herein,N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide(i.e., indinavir) and related compounds, disclosed in European PatentApplication No. EP541168, published May 12, 1993, and U.S. Pat. No.5,413,999, issued May 9, 1995 which are both incorporated herein byreference; N-tert-butyl-decahydro-2- 2(R)-hydroxy-4-phenyl-3(S)-N-(2-quinolylcarbonyl)-L-asparaginyl!amino!butyl!-(4aS,8aS)-isoquinoline-3(S)-carboxamide(i.e., saquinavir) and related compounds, disclosed in U.S. Pat. No.5,196,438, issued Mar. 23, 1993, which is incorporated herein byreference;5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamideand related compounds, disclosed in European Patent Application No.EP532466, published Mar. 17, 1993, which is incorporated herein byreference;1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide(i.e., 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu),5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide(i.e., iQoa-Mta-Apns-Thz-NHtBu) and related compounds, disclosed inEuropean Patent Application No. EP490667, published Jun. 17, 1992 andChem. Pharm. Bull. 40 (8) 2251 (1992), which are both incorporatedherein by reference; 1S- 1R*(R*),2S*!}-N¹ 3-(1,1-dimethylethyl)amino!carbonyl!(2-methylpropyl)amino!-2-hydroxy-1-(phenylmethyl)propyl!-2-(2-quinolinylcarbonyl)amino!-butanediamide (i.e., SC-52151) and relatedcompounds, disclosed in PCT Patent Application No. WO92/08701, publishedMay 29, 1992 and PCT Patent Application No. WO93/23368, published Nov.25, 1993, both of which are incorporated herein by reference; ##STR76##(i.e., VX-478) and related compounds, disclosed in PCT PatentApplication No. WO94/05639, published Mar. 17, 1994, which isincorporated herein by reference; ##STR77## (i.e., DMP-323) or ##STR78##(i.e., DMP-450) and related compounds, disclosed in PCT PatentApplication No. WO93/07128, published Apr. 15, 1993, which isincorporated herein by reference; ##STR79## (i.e., AG1343,(nelfinavir)), disclosed in PCT Patent Application No. WO95/09843,published Apr. 13, 1995 and U.S. Pat. No. 5,484,926, issued Jan. 16,1996, which are both incorporated herein by reference; ##STR80## (i.e.,BMS 186,318) disclosed in European Patent Application No. EP580402,published Jan. 26, 1994, which is incorporated herein by reference;##STR81## (i.e., SC-55389a) disclosed at 2nd National Conference onHuman Retroviruses and Related Infections, (Washington, D.C., Jan.29-Feb. 2, 1995), Session 88; and ##STR82## (i.e., BILA 1096 BS) andrelated compounds disclosed in European Patent Application No. EP560268,published Sep. 15, 1993, which is incorporated herein by reference; and##STR83## (i.e., U-140690) and related compounds disclosed in PCT PatentApplication No. WO 9530670, published Nov. 16, 1995, which isincorporated herein by reference; or a pharmaceutically acceptable saltof any of the above.

In a most preferred combination, a compound of this invention isadministered in combination with ritonavir. Such a combination isespecially useful for inhibiting HIV protease in a human. Such acombination is also especially useful for inhibiting or treating an HIVinfection in a human. When used in such a combination the compound ofthis invention and ritonavir can be administered as separate agents atthe same or different times or they can be formulated as a singlecomposition comprising both compounds.

When administered in combination with a compound of this invention,ritonavir causes an improvement in the pharmacokinetics (i.e., increaseshalf-life, increases the time to peak plasma concentration, increasesblood levels) of the compound of this invention.

Preferred dosage forms for ritonavir include (a) a liquid dosage formfor oral administration as disclosed in U.S. Pat. No. 5,484,801, issuedJan. 19, 1996, which is incorporated herein by reference, (b) anencapsulated solid or semi-solid dosage form as disclosed in PCT PatentApplication No. WO95/07696, published Mar. 23, 1995 and U.S. Ser. No.08/402,690, filed Mar. 13, 1995, both of which are incorporated hereinby reference and (c) an encapsulated solid dosage form as disclosed inPCT Patent Application No. WO95/09614, published Apr. 13, 1995 and U.S.Pat. No. 5,559,158, issued Sep. 24, 1996, both of which are incorporatedherein by reference.

Other examples of preferred dosage forms for ritonavir are disclosed inU.S. patent application Ser. No. 08/754,390, filed Nov. 21, 1996, in thenames of J. Lipari, L. A. Al-Razzak, S. Ghosh and R. Gao and which isentitled Pharmaceutical Composition, which is incorporated herein byreference.

A preferred composition for ritonavir comprises a solution of (a)ritonavir in the amount of from about 1% to about 30% (preferably, fromabout 5% to about 25%) by weight of the total solution and (b) polyoxyl35 castor oil in the amount of from about 0% to about 20% (preferably,from about 5% to about 10%) by weight of the total solution, in apharmaceutically acceptable organic solvent which comprises (i) oleicacid in the amount of from about 15% to about 99% (preferably, fromabout 30% to about 70%; more preferably, from about 40% to about 65%) byweight of the total solution or (ii) a mixture of (1) oleic acid in theamount of from about 15% to about 99% (preferably, from about 30% toabout 70%; more preferably, from about 40% to about 65%) by weight ofthe total solution and (2) ethanol or propylene glycol or a mixturethereof in the amount of from about 0% to about 12% (preferably, about10%) by weight of the total solution. In an even more preferredembodiment of the invention, the solution is encapsulated in a softelastic gelatin capsule (SEC) or a hard gelatin capsule and the solutionalso comprises an antioxidant (preferably, BHT (butylatedhydroxytoluene)) in the amount of from about 0.01% to about 0.08% byweight of the total solution (preferably, from about 0.01% to about0.05% by weight of the total solution).

Examples of such a composition and its preparation are provided below.

    ______________________________________    Component             % By weight    ______________________________________    ritonavir (free base) 20    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          5    Oleic acid, 6321, NF  65    Butylated hydroxy toluene (BHT), NF                          0.01    ______________________________________

Preparation of the above composition

The mixing tank was purged with nitrogen. Oleic acid (649.9 g) andethanol (100 g) were mixed in the tank. This solution was warmed toabout 33° C. (29-37° C.) and maintained at that temperature. Thebutylated hydroxytoluene (0.1 g) was charged into the tank and mixeduntil the solution was clear. The ritonavir (200 g) was slowly chargedinto the tank and mixed until the solution was clear. The polyoxyl 35castor oil (50 g) was added to the tank and mixed. Heating wasdiscontinued and the solution allowed to cool to amibient temperature(20-30° C.). The resulting solution was filled into soft elasticcapsules (0.5 g of solution/SEC) to provide a dosage of 100 mg ofritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg ofritonavir/SEC.

    ______________________________________    Component             % By Weight    ______________________________________    ritonavir (free base) 20    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          10    Oleic acid, 6321, NF  60    Butylated hydroxy toluene (BHT), NF                          0.01    ______________________________________

Preparation of the above composition

The mixing tank was purged with nitrogen. Oleic acid (599.9 g) andethanol (100 g) were mixed in the tank. This solution was warmed toabout 33° C. (29-37° C.) and maintained at that temperature. Thebutylated hydroxytoluene (0.1 g) was charged into the tank and mixeduntil the solution was clear. The ritonavir (200 g) was slowly chargedinto the tank and mixed until the solution was clear. The polyoxyl 35castor oil (100 g) was added to the tank and mixed. Heating wasdiscontinued and the solution allowed to cool to amibient temperature(20-30° C.). The resulting solution was filled into soft elasticcapsules (0.5 g of solution/SEC) to provide a dosage of 100 mg ofritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg ofritonavir/SEC.

Examples of preferred single dosage forms comprising both ritonavir anda compound of the formula I are also disclosed in U.S. patentapplication Ser. No. 08/754,390, filed Nov. 21, 1996, now abandoned inthe names of J. Lipari, L. A. Al-Razzak, S. Ghosh and R. Gao and whichis entitled Pharmaceutical Composition, which is incorporated herein byreference.

A preferred composition for a single dosage form comprising bothritonavir and a compound of the formula I comprises a solution of (a) amixture of ritonavir in the amount of from about 1% to about 30%(preferably, from about 5% to about 25%) by weight of the total solutionand a compound of the formula I in the amount of from about 1% to about50% (preferably, from about 5% to about 40%) by weight of the totalsolution and (b) polyoxyl 35 castor oil in the amount of about 10% byweight of the total solution, in a pharmaceutically acceptable organicsolvent which comprises a mixture of (1) oleic acid in the amount offrom about 10% to about 88% (preferably, from about 40% to about 65%) byweight of the total solution and (2) ethanol in the amount of about 10%by weight of the total solution. In a most preferred embodiment of theinvention, the solution is encapsulated in a soft elastic gelatincapsule (SEC) or a hard gelatin capsule and the solution also comprisesan antioxidant (preferably, BHT (butylated hydroxytoluene)) in theamount of from about 0.01% to about 0.08% by weight of the totalsolution (preferably, from about 0.01% to about 0.05% by weight of thetotal solution).

Examples of such a composition and its preparation are provided below.

    ______________________________________    Component             % By Weight    ______________________________________    ritonavir (free base) 5    compound of Example 2B (free base)                          30    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          10    Oleic acid, 6321, NF  45    Butylated hydroxy toluene (BHT), NF                          0.01    ritonavir (free base) 15    compound Example 2B (free base)                          15    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          10    Oleic acid, 6321, NF  50    Butylated hydroxy toluene (BHT), NF                          0.01    ritonavir (free base) 15    compound Example 2B (free base)                          15    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          5    Oleic acid, 6321, NF  55    Butylated hydroxy toluene (BHT), NF                          0.01    ______________________________________

Preparation of the above composition

The mixing tank was purged with nitrogen. Oleic acid (549.9 g) andethanol (100 g) were mixed in the tank. The butylated hydroxytoluene(0.1 g) was charged into the tank and mixed until the solution wasclear. The ritonavir (150 g) was slowly charged into the tank and mixeduntil the solution was clear. Compound Example 2B (150 g) was slowlycharged into the tank and mixed until the solution was clear. Thepolyoxyl 35 castor oil (100 g) was added to the tank and mixed. Theresulting solution was filled into soft elastic capsules (1.0 g ofsolution/SEC) to provide a dosage of 150 mg each of ritonavir andcompound Example 2B/SEC.

    ______________________________________    Component             % By Weight    ______________________________________    ritonavir (free base) 15    compound Example 2B (free base)                          5    Ethanol (USP, 200 proof)                          10    polyoxyl 35 castor oil (Cremophor ® EL)                          10    Oleic acid, 6321, NF  60    Butylated hydroxy toluene (BHT), NF                          0.01    ______________________________________

Total daily dose of ritonavir (administered in combination with acompound of this invention) to be administered to a human or othermammal host in single or divided doses may be in amounts, for example,from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mgof ritonavir. Dosage unit compositions may contain such amounts ofsubmultiples thereof to make up the daily dose.

In the compositions which comprise a mixture of ritonavir and thecompound of Example 2B, the ratio (w/w) of ritonavir to the compound ofExample 2B ranges from about 1:16 to about 5:1 (preferably, from about1:6 to about 3:1).

In another most preferred combination, a compound of this invention isadministered in combination with ritonavir and one or more reversetranscriptase inhibitors (preferably, one or more compounds selectedfrom the group consisting of AZT (zidovudine), ddI (didanosine), ddC(zalcitabine), d4T (stavudine) and 3TC (lamivudine)). Such a combinationis especially useful for inhibiting or treating an HIV infection in ahuman. When used in such a combination the compound of this inventionand ritonavir and one or more reverse transcriptase inhibitors can beadministered as separate agents at the same or different times or theycan be formulated as compositions comprising two or more of thecompounds. A particularly preferred therapeutic combination comprises acompound of the formula I (especially, the compound of Example 2B) incombination with ritonavir, AZT and 3TC.

It will be understood that agents which can be combined with thecompound of the present invention for the inhibition, treatment orprophylaxis of AIDS or an HIV infection are not limited to those listedabove, but include in principle any agents useful for the treatment orprophylaxis of AIDS or an HIV infection.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula: ##STR84## wherein R₁and R₂ are independently selected from the group consisting ofloweralkyl, cycloalkylalkyl and arylalkyl;R₃ is loweralkyl, hydroxyalkylor cycloalkylalkyl; R₄ is aryl; R₅ is ##STR85## wherein n is 1, 2 or 3,X is O, S or NH and Y is --O-- or --N(R₆)-- wherein R₆ is hydrogen,loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;and L₁ isa)--O--, b) --S--, c) --N(R₇)-- wherein R₇ is hydrogen, loweralkyl,cycloalkyl or cycloalkylalkyl, d) --O-alkylenyl-, e) --S-alkylenyl- f)--S(O)-alkylenyl-, g) --S(O)₂ -alkylenyl-, h) --N(R₇)-alkylenyl- whereinR₇ is defined as above, i) -alkylenyl-O--, j) -alkylenyl-S--, k)alkylenyl-N(R₇)-- wherein R₇ is defined as above, l) alkylenyl or m)alkenylenyl;or a pharmaceutically acceptable salt, ester or prodrugthereof.
 2. A compound according to claim 1 wherein R₁ and R₂ arearylalkyl, R₃ is loweralkyl, R₄ is aryl, R₅ is ##STR86## wherein X, Yand n are defined as therein and L₁ is --O-alkylenyl.
 3. A compoundaccording to claim 1 wherein R₁ and R₂ are benzyl or R₁ is benzyl and R₂is loweralkyl, R₃ is loweralkyl, R₄ is phenyl which is substituted withtwo loweralkyl groups and which is optionally substituted with a thirdsubstituent selected from the group consisting of loweralkyl, hydroxy,amino and halo, R₅ is ##STR87## wherein n is 1 or 2, X is O or S and Yis --NH--, andL₁ is --O--CH₂ --.
 4. A compound according to claim 1wherein R₁ and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃ isloweralkyl, R₄ is 2,6-dimethylphenyl which is optionally substitutedwith a third substituent selected from the group consisting ofloweralkyl and halo, R₅ is ##STR88## wherein n is 1 or 2, X is O or Sand Y is --NH--, andL₁ is --O--CH₂ --.
 5. A compound according to claim1 wherein R₁ and R₂ are benzyl or R₁ is benzyl and R₂ is isopropyl, R₃is loweralkyl, R₄ is 2,6-dimethylphenyl which is optionally substitutedwith a third substituent selected from the group consisting ofloweralkyl and halo, R₅ is ##STR89## wherein n is 1 or 2, X is O or Sand Y is --NH-- and L₁ is --O--CH₂ --.
 6. A compound selected from thegroup consistingof:(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl!amino-1,6-diphenylhexane;(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl)-3,3dimethylbutanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-thionyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(2,4,6-trimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-imidazolidin-2-onyl-3-methylbutanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(4-fluoro-2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-immidazolidin-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(trans-3-(2,6-dimethylphenyl)propenoyl)amino-3-hydroxy-5-(2S-1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(3-(2,6-dimethylphenyl)propanoyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimidin-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane;(2S,3S,5S)-2-(2,6-Dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1-phenyl-6-methylheptane;ora pharmaceutically acceptable salt, ester or prodrug thereof.
 7. Thecompound(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;or a pharmaceutically acceptable salt,ester or pyodrug thereof.
 8. The compound(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane;or a pharmaceutically acceptable saltthereof.
 9. A pharmaceutical composition for inhibiting HIV proteasecomprising a pharmaceutical carrier and a therapeutically effectiveamount of the compound of claim
 1. 10. A pharmaceutical composition forinhibiting HIV protease comprising a pharmaceutical carrier and atherapeutically effective amount of the compound of claim
 7. 11. Apharmaceutical composition for inhibiting HIV protease comprising apharmaceutical carrier and a therapeutically effective amount of thecompound of claim
 8. 12. A method for inhibiting HIV protease comprisingadministering to a human in need of such treatment a therapeuctiallyeffective amount of the compound of claim
 1. 13. A method for inhibitingHIV protease comprising administering to a human in need of suchtreatment a therapeuctially effective amount of the compound of claim 7.14. A method for inhibiting an HIV infection comprising administering toa human in need of such treatment a therapeuctially effective amount ofthe compound of claim
 1. 15. A method for inhibiting an HIV infectioncomprising administering to a human in need of such treatment atherapeuctially effective amount of the compound of claim
 7. 16. Amethod for inhibiting HIV protease comprising administering to a humanin need of such treatment a therapeuctially effective amount of thecompound of claim
 8. 17. A method for inhibiting an HIV infectioncomprising administering to a human in need of such treatment atherapeuctially effective amount of the compound of claim 8.